Abstract
Many oncogenes are involved in the progression from low-grade squamous intraepithelial lesions (LSILs) to high-grade squamous intraepithelial lesions (HSILs); which greatly increases the risk of cervical cancer (CC). Thus, a reliable biomarker for risk classification of LSILs is urgently needed. The prolyl isomerase Pin1 is overexpressed in many cancers and contributes significantly to tumour initiation and progression. Therefore, it is important to assess the effects of cancer therapies that target Pin1. In our study, we demonstrated that Pin1 may serve as a biomarker for LSIL disease progression and may constitute a novel therapeutic target for CC. We used a the novel Pin1 inhibitor KPT-6566, which is able to covalently bind to Pin1 and selectively target it for degradation. The results of our investigation revealed that the downregulation of Pin1 by shRNA or KPT-6566 inhibited the growth of human cervical cancer cells (CCCs). We also discovered that the use of KPT-6566 is a novel approach to enhance the therapeutic efficacy of cisplatin (DDP) against CCCs in vitro and in vivo. We showed that KPT-6566-mediated inhibition of Pin1 blocked multiple cancer-driving pathways simultaneously in CCCs. Furthermore, targeted Pin1 treatment suppressed the metastasis and invasion of human CCCs, and downregulation of Pin1 reversed the epithelial-mesenchymal transition (EMT) of CCCs via the c-Jun/slug pathway. Collectively, we showed that Pin1 may be a marker for the risk of progression to HSIL and that inhibition of Pin1 has anticancer effects against CC.
Highlights
Many oncogenes are involved in the progression from low-grade squamous intraepithelial lesions (LSILs) to high-grade squamous intraepithelial lesions (HSILs); which greatly increases the risk of cervical cancer (CC)
Pin1 and c-Jun in SILs and cervical cancer patient tissues; Pin1 positivity was significantly associated with higher HSIL progression rates in LSIL patients
Pin1 expression was correlated with poor outcomes for LSIL patients (P= 0. 001), whereas c-Jun expression was irrelevant to the outcomes of LSIL patients (P= 0.599) (Table 1)
Summary
Many oncogenes are involved in the progression from low-grade squamous intraepithelial lesions (LSILs) to high-grade squamous intraepithelial lesions (HSILs); which greatly increases the risk of cervical cancer (CC). Due to the activation and feedback of multiple cancer-driving pathways, about 30% of patients experience lymph node recurrence and distant metastasis after cisplatin-based treatment. This treatment fails to fully eradicate the disease [6]. Previous work performed by our lab has shown that the expression of Pin in the CRL cell line, which is resistant to Herceptin, was significantly higher than that of BT-474 in triple positive breast cancer cell lines (data not shown) These data strongly provide a compelling rationale for the study research of Pin1-targeted therapies
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