Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

Abstract

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease‐free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer‐driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal‐epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer‐driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

“…In this study, we elucidated the role of Pin1 on IL‐18 expression via the NF‐κB signalling pathway in PDAC. Consistent with our previous research and with the results from Chen's study, 16,17 we found that the expression of Pin1 is elevated in PDAC compared to adjacent normal tissues. We previously demonstrated that elevated Pin1 expression in PDAC was an indicator of a poor prognosis and a sign of a maintained redox balance via the c‐Myc/NRF2/ARE axis, which provides antioxidation protection in Kras‐mutant pancreatic cancer cells 16 .…”

“…The most challenging features of PDAC are its early invasion and migration; thus, finding a feasible therapeutic strategy targeting tumour metastasis could assist in improving the prognosis of patients with PDAC 43 . Pin1 has been reported to promote pancreatic cancer metastasis in vitro and in vivo 17 . In addition, IL‐18 was reported to be capable of stimulating the invasion and metastasis of PDAC and hepatic carcinoma 20,44 .…”

“…Pin1 promoted pancreatic cancer cell proliferation, which was partially due to mitochondrial dysfunction, and Pin1 also maintained a redox balance via synergistic activation of c‐Myc and NRF2 to counteract Kras ‐induced mitochondrial respiratory injury 16 . Another recent study reported that both genetic and chemical ablation of Pin1 dramatically inhibited tumorigenesis and metastasis in a mouse model of PDAC 17 . However, no study has concentrated on Pin1‐NF‐κB‐mediated tumour progression and metastasis in PDAC.…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…According to Chen et al [196], upregulated PIN1 was associated with cell migration, invasion, and metastasis occurrence in the case of pancreatic ductal carcinoma. In fact, PIN1 overexpression may be an essential cause for the tumorigenesis and cancer stemness development in breast and pancreatic carcinomas [186,195,196]. Studies of the roles of SPOP and PIN1 in prostate cancer stemness and progression have revealed that PIN1 is an upstream regulator of NANOG and also protects the latter from SPOP-mediated polyubiquitination and degradation, thus promoting NANOG-conferred cancer stemness features in prostate tumors [197].…”

“…Later, the same research group reported further unraveling of the PIN1-dependent mechanism driving breast CSCs: Overexpressed PIN1 upregulates the transcription of genes encoding Rab2A (a small GTPase), and then excess Rab2A interacts with ERK1/2 to prevent the inactivating dephosphorylation of ERK1/2, which remains active and thus mediates ZEB1 upregulation and nuclear translocation of β-catenin [195]. According to Chen et al [196], upregulated PIN1 was associated with cell migration, invasion, and metastasis occurrence in the case of pancreatic ductal carcinoma. In fact, PIN1 overexpression may be an essential cause for the tumorigenesis and cancer stemness development in breast and pancreatic carcinomas [186,195,196].…”