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Review
Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126
Peptidyl-prolyl isomerase (PPIase): an emerging area in tumor biology
Pulak Ranjan Nath1*
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
*Corresponding author: *Corresponding author: Dr. Pulak Ranjan Nath, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20812, USA. Tel:+1 (301) 480 4353, Fax:+1 (301) 480 0611; E-Mail: or
Citation: Pulak Ranjan Nath. Peptidyl-prolyl isomerase (PPIase): an emerging area in tumor biology. Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126
Copyright: @ 2017 Pulak Ranjan Nath. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing Interests: The author declares no competing financial interests.
Received May 5, 2017; Revised Sept 10, 2017; Accepted Oct 2, 2017. Published Nov 6, 2017
Abstract
Peptidyl-prolyl isomerase (PPIase) catalyzes the interconversion of a specific Pro-imide bond between the cis and trans conformations. Such conformational interconversion by PPIases at the backbone of key signaling proteins is an emerging area of active research. Two families of PPIases, cyclophilins and FK506-binding proteins (FKBPs), have been extensively studied due to their high affinity for immunosuppressive drugs, cyclosporine A and FK506, respectively. These two families of PPIases and also Pin1 within the parvulin-family mediate temporal and spatial conformational modifications of signaling proteins; therefore, affecting the downstream signaling events. PPIases have recently been implicated in multiple aspects of cell cycle regulation and cellular processes related to a number of human pathologies, including cancer. This review highlights the causal relationship between PPIases and malignant transformation and progression. Based on the current understanding, it is postulated that a cancer intervention strategy based on the development of isomerase-specific inhibitors is not far away.
Keywords: PPIases, Cyclophilin, FKBP, Pin1
Introduction
A properly folded protein under physiological conditions must maintain its functional integrity as a part of the entire proteome. Pathophysiological alterations, such as malignancy, have been shown to remodel folding-mediated signaling pathways. Typically, certain peptide bonds on the backbone of a native protein can adopt cis/trans isomerism, which resembles a molecular switch for bioactivity (1). Any alteration of the productive folding and restructuring pathways may result in misfolded and dysfunctional proteins that are implicated to play critical role in malignancy (2). Distinct posttranslational modification mechanisms involving a large number of proteins tightly regulate cell growth and differentiation. Posttranslational protein modifications not only increase in the diversity of the proteome, but serve also as efficient mechanisms for temporal and spatial regulation of activity in many types of effector molecules. Among the most common mechanisms of protein modifications, peptidyl-prolyl cis-trans isomerization, mediated by a family of enzymes termed as PPIases, has been a topic of active research. PPIase includes a large number of highly conserved proteins, which are widely distributed throughout organisms. These are structurally related proteins and share an isomerization domain [Fig. 1]. PPIases are also found to be overexpressed in a variety of human tumors [Fig. 2, Table 1], and are implicated to play critical role in tumor generation and progression.
Figure 1. Schematic representation of structures of PPIases playing important roles in tumor development and progression. Schematic diagrams depicting structures of the selective of cyclophilin, FKBP and purvulin family-member proteins that are involved in tumor growth and metastasis. Sizes of the unprocessed protein are shown in brackets next to the gene name. In the second row, the accession numbers of UniProtKB/Swiss-Prot database and NCBI Reference Sequence are given. Amino acid residues that border the protein domains or modules are designated according to UniProtKB/Swiss-Prot, Pfam or ClustalW alignment. The PPIase domain is indicated in red. Functionally important amino acid residues of Cyps, FKBPs and Pin1 are indicated. rrm, RNA recognition motif; TPR, tetratricopeptide repeat; EF, EF hand; WD40, WD40 repeat.
Figure 2. Expression profiles of the prototypic members cyclophilin, FKBP and parvulin family across various types of human tumors. Staining profiles for CypA, FKBP12 and Pin1 in human tumor tissues based on immunohistochemisty using tissue micro arrays and archived from The Human Protein Atlas (http://www.proteinatlas.org). Each bar represents data from at least 10 patient samples.
The unique property of PPIases (EC 5.2.1.8) attributes to their ability to modify protein structure by cis-trans-isomerization of peptide bonds preceding to a specific proline residue. Though, a trans (ω = 180◦) conformation is energetically favored, below 10% of the newly synthesized proteins containing a peptidyl-prolyl bond, acquire a cis (ω = 0◦) conformation during normal physiological processes in the eukaryotes. The high-energy barrier between the cis and trans states (3) mostly limits a spontaneous cis-trans protein interconversion (4-6). Thanks to an active PPIase, which greatly reduces the free energy requirement and accelerates the interconversion of protein states (7-9) and results in more biologically meaningful consequences. Recently, we have shown that PPIases play important role in T cell signaling pathways by conformational regulation of adaptor protein CrkII (10-12). However, controversies on the true catalytic mechanism driving cis-trans isomerization are still prevalent (13-17).
PPIases are grouped into three subfamilies: cyclophilins (Cyps), FK506 binding protein (FKBPs), and parvulins (18-20). We have recently listed several distinct functional proteins of Cyps, FKBPs and parvulins that play an important role in immune cells, cellular localization and chromosomal locations of encoding genes (21). We found that the prototypic members of PPIase families, CypA, FKBP12 and Pin1 are ubiquitously expressed in mouse organs and tissues [Fig. 3]. Interestingly, members of three families of PPIases share conserved regions within enzymatic domains [Fig. 1], suggesting a broad substrate specificity and functional redundancy (21).
Figure 3. Protein expression profile of the prototypic members of cyclophilin, FKBP and parvulin family across various organs and tissues of mice. Lysates from organs and tissues of eight weeks-old C57BL/6 male mice were prepared and 30 μg proteins per lane were subjected to SDS-PAGE. Proteins were then electroblotted onto nitrocellulase membrane and CypA, FKBP12 and Pin1 proteins were visualized using specific Abs reactive against mouse proteins after sequential stripping and blotting (panels A, B & C). Reblotting of the stripped membrane with mouse mAb anti-Actin was performed as a protein loading control (panel D). Immunoreactive protein bands were detected using HRP-conjugated secondary Abs and immunoperoxidase ECL detection system, followed by autoradiography. Results are representative of three independent experiments.
Cyps and FKBPs, also known as “immunophilins”, have high binding affinity for the immunosuppressive drugs cyclosporine A (CsA) and FK506, respectively (22). Immunophilins were initially identified as molecular chaperones (20) though their isomerization-based role in folding of nascent proteins was appreciated. Immunophilins interact with calcineurin at the basal level, however the affinity of such interaction increases upon binding of CsA and FK506. Immunophilin-calcineurin interaction results in the inhibition of calcineurin to activate NF-AT (23) and subsequent transcription of the IL-2 gene (24) altering survival and differentiation of CD4+ and CD8+ T cells (25). We have recently discussed the molecular pathways that are affected by the CsA-Cyp and FK506-FKBP interactions elsewhere (21). Members of the third subfamily of PPIases, parvulins including Pin1, are structurally and functionally distinct from Cyps or FKBPs. Unlike the immunophilins, the catalytic activity of Pin1 is kinase activation-dependent and isomerizes phospho-serine/threonine-proline motif-containing proteins. The role of immunophilins and Pin1 in the regulation of immune cell functions and their involvement in the regulation of other normal and pathological cellular functions have recently been discussed elsewhere (21,26-29). This review takes a close look into the connections between PPIases and tumor generation and progression.
Table 1. List of human cancers that exhibit overexpression of specific family of PPIases.
Cyclophilins and malignancies
Cyclophilins (Cyps) are the intracellular ligands for the immunosuppressive drug cyclosporine A (CsA). They function as molecular chaperones for proper folding of proteins and also catalyze isomerization of peptide bonds preceding proline (30-32). Cyps are highly conserved proteins throughout evolution. There are around 20 putative genes of Cyps distributed throughout the human genome that encode a total of about 16 Cyp proteins in humans (21,33). Cyp proteins are localized in specific cellular compartments including the cytosol, endoplasmic reticulum (ER), mitochondria and nucleus and show specific pathological significance (21). Their physiological role involves, but not limited to, muscle differentiation, detoxification of reactive oxygen species (ROS) (34) and immune response (21). The nuclease activity of Cyps is similar to apoptotic endonucleases implicated by their function to apoptotic DNA degradation. Secreted Cyps, e.g. CypA, are present in human serum in nanomolar range, which is elevated during inflammatory diseases (35). Extracellular CypA promotes chemotactic activity of leucocytes by interacting with its major signaling receptor CD147 (36). Such interaction in macrophages promotes development of rheumatoid arthritis within the synovium (37). Similarly, CypA deficient mice had limited recruitment of inflammatory cells (CD45+) in the cardiovascular wall (38). Secreted CypA plays important role for vascular inflammation and pathogenesis in diabetic patients (39). Cyps also play important roles in viral infection in the host. CypA is incorporated into viral particles and either increases HIV and vaccinia virus infectivity (40,41) or suppresses rotavirus and influenza virus (42,43). Cyps are also well documented among the major overexpressed proteins in multiple types of cancer; however, their precise role in cellular transformation is not well defined.
CypA
Cyclophilins have been found to be associated with a variety of cancer types including lung, breast, liver, and prostate (44). Extended CypA mRNA expression profiling performed by serial analysis of gene expression indicated that over 80% of cancer tissue types exhibited an elevated expression of CypA compared to normal tissue samples (45). The prototypic CypA is indicative of malignant transformation (44), and thus has been suggested to be a prognostic marker (46) for tumor formation. In a clinical study, treatment of female patients who were chronically immunosuppressed with CsA in combination with other drugs, showed a surprisingly low incidence of de novo breast cancers (47). Regulation of the prolactin receptor (PRLr)/ Janus kinase 2 (Jak2) complex by CypA has been shown to decrease the risk of female breast cancer. PRL induced expression of the transcription factor STAT5 was directly correlated to the level of intracellular CypA (48). CypA is also overexpressed in pancreatic cancer cell lines and in human pancreatic adenocarcinoma as compared to normal tissues. Exogenous addition of CypA significantly stimulated cancer cell proliferation (49). CypA was also identified as a novel hepatocellular carcinoma marker that was overexpressed in patient-derived tissue, compared to normal counterparts (50). As expected, siRNA mediated suppression of CypA in non-small cell lung tumor resulted in reduced cell growth (51). CypA is also overexpressed in metastatic melanoma (52), gastric adenocarcinoma (53) and in clinical endometrial carcinoma specimens (46).
The hypoxia-inducible factor 1α (HIF1-α) (54) and the tumor suppressor p53 are involved in CypA overexpression or exosome-mediated CypA secretion in various cancer cells. CypA physically and functionally interacts with p53 by limiting its DNA binding ability and enhancing the anti-apoptotic cellular responses (55).
CypB
CypB is also implicated in the proliferation and survival of breast, liver, brain, and myeloma cancer. siRNA mediated repression of CypB in ductal breast epithelial tumor cells decreased cell growth, proliferation and motility (58). CypB is found to interact with the transcription factor STAT3 in HepG2 liver cells and inhibition of CypB in STAT3-dependent human myeloma cell lines resulted in apoptosis, suggesting that CypB acts as a pro-survival protein in these cells (59). CypB is also overexpressed in malignant glioma tissue and suppression of CypB resulted in reduced cell growth and increased mortality in vitro and in vivo (60).
CypB-STAT3 interaction was found to be of low affinity in multiple myeloma cells. Administration of CsA in multiple myeloma cells led to apoptotic cell death of these cells. A catalytically compromised CypB mutant did not show any effect on STAT3 transcriptional activity, suggesting that CypB requires its PPIase activity to act on STAT3 (59).
Other Cyps
CypC overexpression in circulating tumor cells after chemotherapy is associated with poor survival of ovarian cancer patients and has been identified as a novel gene marker for detecting circulating tumor cells (61). CypD is also significantly upregulated in ovarian cancer (62), breast cancer (62), uterus cancer (62) and prostate cancer (63). Cyp33 is significantly upregulated in glioblastoma compared to non-neoplastic brain tissue (64). Peptidyl prolyl cis-trans isomease-like protein1 (PPIL1) is overexpressed in patient-derived colon cancer tissue, and siRNA mediated suppression of PPIL1 in the human colon cell line SNUC4 suppressed cell growth (65). Interaction of androgen receptor with Cyp40 and FKBP51 augmented androgen-dependent prostate cancer and treatment of prostate cancer cell lines with CsA and FK506 consequently inhibited androgen-dependent cell growth and gene transcription (63). The combination of sanglifehrin and CsA, two potent inhibitors of most cyclophilin isoforms, synergistically increased apoptotic cell death. Decreased cyclophilins in hepatocellular carcinoma (HCC) and glioma cell lines induced apoptosis, indicating that these PPIases are essential in tumorigenesis (56,57). Studies investigating the involvement of various Cyp isoforms may help explain the synergism between the reduction of Cyps and apoptosis induction.
Cyps and chemoresistance
Cyclophilins are also associated with cancer chemoresistance. For example, overexpression of CypA is associated with resistance of prostate cancer cells to cisplatin-induced cell death. It is proposed that CypA suppresses cisplatin-induced ROS production and the loss of mitochondrial membrane potential (54). Consistent with that finding, loss of CypA expression was found to increase mitochondrial membrane depolarization and reduce survival following H2O2 treatment (54). CypA is down regulated in melphalan-resistant MCF7 breast cancer cells when compared to non-resistant cells (66). This down regulation of CypA allows evasion of apoptosis in MCF7 by inhibition of apoptosis-inducing factor (AIF) (67). Furthermore, CypA-overexpressing endothelial liver cells display resistance to doxorubicin and vincristine (68). CypA is also overexpressed in endometrial cancer cells, HEC-1-B/TAX and AN3CA/TAX, and promotes cellular resistance to paclitaxel. siRNA-mediated knockdown of CypA significantly inhibited cell proliferation and invasion upon treatment with paclitaxel. Mechanistic investigation revealed that paclitaxel treatment of CypA deficient endometrial cancer cells reduces phosphorylation of Akt and the MAPK ERK1/2, p38 and JNK suggesting that overexpression of CypA enhances MAPK activity (69).
Under hypoxic conditions, HIF-1α upregulates CypB in human hepatocellular carcinoma. Knockdown of CypB significantly reduced cell survival when subjected to hypoxia, cisplatin, or H2O2 treatment (70), suggesting that CypB may play a similar role to CypA in cisplatin resistance by protecting the cells against ROS induced stress (54). Moreover, the role of some PPIases in tumor progression strictly correlates with their subcellular localization. Expression of CypD, for example, is restricted to mitochondria and is directly involved in resistance to apoptotic stimuli through regulation of the mitochondrial permeability transition pore (71). These studies confirm that upregulation of cyclophilins is associated with tumor progression, acquired chemoresistance and resistance to apoptosis. Cyclophilins may therefore represent valuable biomarkers for chemoresistance and potential therapeutic targets to sensitize cancer cells to chemotherapy.
FKBPs and malignancies
Like Cyps, FKBPs also function as molecular chaperones and catalyze the Pro-imide bonds. FKBPs of bacterial origin can activate mitogenic signaling pathways, ERK and EGF-R, upon infection of gastric epithelial cells and promote cellular transformation (72). FKBPs are mostly known as cellular targets for FK506 and Rapamycin. FK506 and Rapamycin gained attention over the last decade as anti-cancer immunosuppressant agents (73-75). Both drugs are widely used following organ transplantation for preventing allograft rejection. The FK506-FKBP complex inhibits calcineurin phosphatase activity and Rapamycin-FKBP complex inhibits mTOR activity. Both calcineurin (75-77) and mTOR (73,74,78) are implicated in tumor growth and metastasis. There are about 15 putative genes of FKBPs distributed throughout the human genome that encode a total of at least 16 proteins with molecular weight ranging from 12 to 133 kDa (21,79).
FKBP12
FKBP12 is highly expresssed in childhood astrocytoma (80). The expression profiles of 13 childhood astrocytomas showed that the protein level of FKBP12 was associated with increased expression of hypoxia-inducible transcription factor (HIF)-2α and epidermal growth factor receptor (EGFR) in malignant high-grade astrocytomas. Among multiple FKBPs that were highly expressed in astrocytoma cells, FKBP12 appeared to have a pathogenetic role in tumor aggressiveness. FKBP12/HIF2/EGFR was involved in angiogenesis of childhood high-grade astrocytomas, suggesting that these genes may represent a potentially new therapeutic target.
FKBP12 mediates the ability of chronic lymphocytic leukemia (CLL) cells to escape from the homeostatic control of TGF-β (81). FK506 has been shown to reactivate the TGF-β signal in CLL, and induce apoptosis through the mitochondria-dependent pathway in 33 out of 62 patient samples. FKBP12 acts as a natural ligand for the TGF-β type I receptor (TβR-I) (82). Association of FKBP12 with TβR-I is via a glycine- and serine-rich motif of TβR-I, which caps its phosphorylation and stabilizing its inactive conformation of TβR-I. The PPIase core domain of FKBP12 is important for the interaction of the immunophilin with TβR-I. FK506 inhibits this interaction and promotes receptor trans-autophosphorylation (82), which in turn resulted in apoptosis of both normal and leukemic lymphocytes.
FKBP24
FKBP24, a molecule downstream to EGFR signaling pathway, was identified in glioblastoma and as molecular determinant responsible for resistance of glioblastoma to Erlotinib, a small molecule inhibitor of EGFR tyrosine kinase activity (83).
FKBP25
FKBP25 was identified as a transcriptional target of Multiple Myeloma Oncogene 1/ Interferon Regulatory Factor 4 (MUM1/IRF4) (84). Increased MUM1 expression was observed in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes (85).
FKBP25 stimulated auto-ubiquitylation and proteasomal degradation of mouse double minute 2 homolog (MDM2), leading to the induction of p53 and its downstream effector p21 (86). On the other hand, FKBP25 levels were decreased by p53 activation. This finding is in line of reduction of FKBP25 levels in both human and murine immortalized and transformed cell lines following induction of wild-type p53 by several DNA damaging stimuli (87).
FKBP36
FKBP36 promoter is frequently methylated in cervical neoplasia (88). This PPIase forms complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons that repress transposable elements and prevent their mobilization, which is essential for the germ-line integrity (89).
FKBP37
The aryl hydrocarbon receptor (AHR) interacting protein AIP, also known as FKBP37, displays structural similarity to FKBP52 but has distinct cellular roles. In pituitary adenoma, AIP gene functions as a tumor-suppressor gene (90). Germline AIP mutations result in the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents. Around 75% of AIP mutations completely disrupt the C-terminal TPR domain, leading to failure of protein-protein interactions, a mechanism appeared to be sufficient to predisposition to pituitary adenoma (91).
FKBP38
FKBP38 exerted an anti-apoptotic effect on epithelial carcinoma HeLa cells. Mechanistic investigation revealed that FKBP38 anchors Bcl-2 and Bcl-xL to mitochondria and protect mitochondria from induction of permeability transition (92). The authors found that overexpression of FKBP38 prevented HeLa cells from apoptosis. Consistently, functional inhibition of FKBP38 by a dominant- negative mutant or RNA interference promoted apoptosis (92).
FKBP51
FKBP51 has been well documented in cancer growth and aggressiveness (93). In glioma (94), prostate cancer (63) and melanoma (95), a strict correlation between the tumor hostility and protein abundance has been demonstrated. Overexpression of FKBP51 increased androgen signaling in cells and contributes to prostate carcinogenesis (96). FKBP51 physically associates with the androgen receptor before ligand binding in prostate cancer cell line LNCaP and prostate tumor tissue (97). Periyasamy et al. found that FKBP51 was upregulated in prostate cancer in association with cyclophilin Cyp40 (63). Expression of FKBP51 in androgen-dependent tumor cell lines directly correlated with androgen-dependent transcriptional activity, while knockdown of FKBP51 dramatically decreased androgen-dependent gene transcription and proliferation (63).
FKBP51 regulates the anti-apoptotic effects in leukemia (98), melanoma (99), glioma (94), prostate cancer (63) and retinal tumors (100). This is also necessary for chemotherapy (98,101), radiotherapy (99) and induction of NF-κB transcription factor, which in turn promoted transcription of anti-apoptotic proteins and induced autophagy (99).
The metastatic potential of melanoma positively correlates with the FKBP51 level (102). An interaction between p300 and FKBP51 suggested that the immunophilin participated to chromatin remodeling events. Additionally, FKBP51 increased the tumor promoter potential of the TGF-β (103).
A tumor suppressor role for FKBP51 in pancreatic cancer has recently been suggested. FKBP51 acts as a scaffold for the phosphatase PHLPP, facilitating Akt de-phosphorylation in vitro, and favoring apoptotic response to gemcitabine (104).
FKBP52
FKBP52, along with Cyp40, is highly expressed in breast cancer cell lines (105). Data showed that FKBP52 was among the highest expressing proteins in breast cancer stem cells (106). Another study by Yang et al. suggested that FKBP52 is a biomarker for predictive breast cancer response to doxorubicin (107).
Both, mRNA and protein expression of FKBP52 was found to be elevated in early-stage breast tissues, such as ductal in situ breast tumors in a clinical study including 60 early-stage primary breast cancers, 82 in situ breast carcinomas and 93 healthy controls. The authors also found FKBP52 auto-antibodies were associated with early stage breast cancer and hypothesized that FKBP52 immunogenicity could be attributed to the increased protein expression (108).
A study on the protein expression profile in the livers of tumor-prone transgenic mouse models of HCC identified FKBP52 as a differentially expressed protein (109). Levels of FKBP52 in serum samples appeared to be increased in HCC, compared with control cases. The regulation of FKBP52 was also found to be relevant to HCC staging, with a dramatic decline at stage III. The study points out FKBP52 may be a biomarker for early HCC diagnosis (109).
FKBP65
High expression of FKBP65 has been observed in benign tumor cells and in ovarian epithelium; however, decreased in ovarian cancer cells (110). FKBP65 is overexpressed in tumors harboring rearrangements of the ETS (E26 transformation- specific) transcription factor in prostate cancer (111). Since it’s an active player in gene fusion, ETS factors have been often found to be associated with cancer. The authors proposed that FKBP65 could serve as diagnostic markers for molecular cancer subtypes in prostate cancer harboring the ETV1 fusion gene rearrangements.
Olesen et al. identified FKBP65 as a novel marker associated with colorectal cancer (112). Analysis of 31 colorectal adenocarcinomas showed a significant up-regulation of FKBP65 in tumors, compared to normal colorectal mucosa. Moreover, immunohistochemical analysis of 26 adenocarcinomas and matching normal mucosae showed that FKBP65 was not present in normal colorectal epithelial cells, but highly expressed in colorectal cancer cells.
FKBPL
Being a divergent member of FKBP family, FK506-binding protein-like (FKBPL) shares homology within the TRP domain with FKBP52/51, however, contains a weaker PPIase domain (113,114). Radiation promotes FKBPL protein binding to p21 and prevents its proteasomal degradation. Knock down of FKBPL presumably reduces p21 and confers resistance to radiation (113). FKBPL is also found to interact with estrogen receptor alpha (115,116). Breast cancer cells stably overexpressing FKBPL become highly sensitive to anti-estrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reversed this phenotype. FKBPL expression correlates with increased overall survival and distant metastasis-free survival in breast cancer patients. Mechanistically, FKBPL promotes breast cancer sensitivity to endocrine therapies and improve outcomes (115,116).
Pin1 and malignancies
Expression of Pin1 increases in lung cancer and is associated with poor prognosis (117). Pin1 levels are found to be high in prostate tumor specimens after prostatectomy and correlates with a higher probability of tumor recurrence (118,119). Such correlation with high Pin1 levels and disease progression has also been found in non-small cell lung cancer and oral squamous cell carcinoma patients (117,120,121). High expression of Pin1 in esophageal squamous cell carcinoma correlates with lymph node metastasis and is an independent prognostic factor for this disease (120). In a broad range analysis of 60 different human tumor types, 38 tumors including prostate, breast, lung, ovary and cervical tumors, and melanoma have Pin1 overexpression in more than 10% of cases compared to the corresponding normal tissues (122,123). In addition, Pin1 expression has been found to correlate with other tumor markers such as β-catenin accumulation in oral squamous cell carcinoma and cyclin D1 levels in esophageal and oral squamous cell carcinoma (120,124,125). Pin1 antagonists, like Juglone, PiB, dipentamethylenethiuram monosulfide and halogenated phenylisothiazolone TME-001, have been found either to inhibit the PPIase activity of Pin1 or to target the Pin1 WW domain and preventing binding of Pin1 to its substrates (126). Elevated levels of Pin1 in tumors provide a therapeutic opportunity to utilize these inhibitors against tumor development. However, Pin1 may have a general regulatory role in healthy cells and therefore the specificity of these antagonists is still in question. More directed preclinical and clinical studies are required before employing these inhibitors in humans.
Mechanistically, Pin1 influences multiple signaling pathways in malignant transformations. Studies in genetically depleted mouse models revealed varying roles of Pin1 in cancer depending on organ, tissue, age and genetic background. Pin1 stabilizes cyclin D1 proteins and regulates transcription factors c-Jun and NF-kB within the cytoplasm. In addition, Lu and Zhou precisely discussed the roles of Pin1 to activate certain oncogenes and inactivate other important tumor suppressors (127).
Pin1 also regulates the Ras-signaling pathways in transformed mammary epithelial cells (128). Ras-induced focal adhesion kinase (FAK)- phosphorylation at a serine residue leads to Pin1 recruitment to FAK. Pin1 PPIase activity is required for dephosphorylation of FAK at the tyrosine 397 residue by the protein tyrosine phosphatase PTP-PEST. Subsequently, inhibition of FAK activity promotes cell migration, invasion and Ras-induced metastasis (129). Additionally, Pin1 associates with Smad2 and Smad3 and are phosphorylated in response to TGF-β. Pin1 activity was shown to be required for the reduction of Smad2/3 protein levels (130). Interestingly, Pin1 was shown to promote migration and invasion of prostate cancer cells induced by TGF-β (131).
Other tumorigenesis-specific Pin1 substrates include Notch1 and p53 (132,133). Pin1 was found to interact with the phosphorylated Ser/Thr-rich region of Notch1 enhancing its transcriptional activity and promoting tumourigenesis. γ-secretase, which cleaves Notch1 and activates downstream signaling pathways, was found to be a Pin1 substrate. Combined inhibition of γ-secretase and Pin1 significantly impaired tumor growth in a breast cancer xenograft model (133). Finally, Pin1 also acts on the conformational modification of p53 and upon phosphorylation after DNA damage it enhances transactivation activity (134).
Conclusions
Despite providing a congenial microenvironment for proper folding of a protein, the active participation in inducing conformational changes of a protein by PPIases is lately appreciated. Though, encoded by distinct genes from different locus, the isomerase domains of PPIases highly resemble their structural and functional traits. The multifunctional nature of PPIases is evident from their unique overall structures, ubiquitous presence and abundant distribution in cells, indicating that isomerization is a critical process in sustaining cellular maintenance machinery. PPIases are bioactive and confer “on”/”off” peptide bond-based switches to their substrates, which undergo a functionally relevant structural change on a one-bond level. The high abundance of PPIases in most human tumor types [Fig. 2, Table 1] indicates their unique regulation in tumor biology. Overexpression of multiple PPIases in individual cancer types indicates their compensatory role and therefore may be challenging for a designing therapeutic strategy with a single agent. The involvement of PPIases in the pathophysiological signaling processes in multiple cancers continues to be in the focus of biomedical research. Increasing clinical evidence of adverse effects including malignancies on transplanted patients under CsA and FK506 treatment indicate a correlation with PPIase inhibition. The molecular mechanisms regulating the overexpression of different PPIases in tumors therefore need to be thoroughly examined in order to design common therapeutic intervention. The non-immunosuppressive PPIase inhibitors as well as small molecule inhibitors will facilitate future studies to dissect potential redundancies of cyclophilins, FKBPs and Pin1 in tumorigenesis.
Acknowledgment
I am thankful to Dr. Anthony Schwartz for excellent editorial assistance. I acknowledge the ‘Kreitman Graduate Fellowship’ for supports during the doctoral research at the Ben-Gurion University, Israel. The author is also a recipient of the ‘PBC Outstanding Postdoctoral Fellowship’ and is thankful to the Planning and Budgeting Committee (PBC), Council for Higher Education, Israel. I also thank Dr. Noah Isakov for his supports during the course of this study.
Conflict of interest
The author declares no conflict of interest.
Abbreviations
AHR: Aryl hydrocarbon receptor;
AIF: Apoptosis-inducing factor;
Akt: serine/threonine-protein kinase;
Bcl-2: B-cell lymphoma 2;
Bcl-xL: B-cell lymphoma-extra large;
CLL: Chronic lymphocytic leukemia;
CsA: Cyclosporine A;
Cyp: Cyclophilin;
EGFR: Epidermal growth factor receptor;
ER: Endoplasmic reticulum;
ERK: Extracellular signal-regulated kinase;
ETS: E26 transformation- specific;
ETV1: ETS translocation variant 1;
FAK: Focal adhesion kinase;
FKBPs: FK506-binding proteins;
HCC: Hepatocellular carcinoma;
HIF1-α: Hypoxia-inducible factor 1α;
IL-2: Interleukin 2;
IRF4: Interferon Regulatory Factor 4;
Jak2: Janus kinase 2;
JNK: c-Jun N-terminal kinases;
MAPK: Mitogen-activated protein kinase;
MDM2: Mouse double minute 2 homolog;
mTOR: mechanistic Target of rapamycin;
MUM1: Multiple Myeloma Oncogene 1;
NF-AT: Nuclear factor of activated T cell;
Notch1: Notch homolog 1, translocation-associated;
PHLPP: PH domain and Leucine rich repeat Protein Phosphatases;
PPIase: Peptidyl-prolyl cis/trans isomerase;
PPIL1: Peptidyl prolyl cis-trans isomease-like protein1;
PRLr: Prolactin receptor;
PTP-PEST: Protein tyrosine phosphatase containing a C-terminal PEST motif;
ROS: Reactive oxygen species;
STAT3/5: Signal transducer and activator of transcription 3/5;
TGF-β: Transforming growth factor beta;
TPR: Tetratricopeptide repeat;
TβR-I: TGF-β type I receptor.
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