CNTN-1 promotes docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer

Abstract

Introduction: Therapy options for prostate cancer (PCa) typically are centered on docetaxel-based chemotherapy but are limited by the effects of multi-drug resistance. Recent advances have illustrated a role of contactin-1 (CNTN-1) in tumor chemoresistance, while the function and mechanism of CNTN-1 in the resistance of docetaxel in prostate cancer have not yet been elucidated. Material and methods: Docetaxel (Dox)-resistant PCa cell lines of PC3 (PC3-DR) and DU145 (DU145-DR) were established, and short hairpin RNA (shR-NA) constructs targeting CNTN-1 were generated to analyze the effect of knockdown of CNTN-1 on PCa progression. Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing, transwell and western blotting analysis were used to analyze cell proliferation, apoptosis, migration, invasion and related protein expression levels, respectively. Results: Knockdown of CNTN-1 in PC3-DR and DU145-DR cells attenuated cell proliferation, migration, invasion, EMT phenotype, and drug resistance, and increased cell apoptosis further reduced the tumorigenic phenotype. Knockdown of CNTN-1 resulted in an anti-tumor effect in the xenograft tumor model, and decreased activity of the phosphoinositide 3-kinase (PI3K)/ Akt signaling pathway both in vitro and in vivo. Conclusions: The results of the present study suggest that downregulation of CNTN-1 may be an important mechanism to reverse chemoresistance in Dox-resistant PCa progression, thus shedding light on the development of novel anti-tumor therapeutics for the treatment of PCa.

Epithelial–Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics

“…The protein has been shown to utilize EMT-dependent promotion for enhanced cell invasion, migration, and metastasis in several different types of carcinoma [ 43 ]. Downregulation of Cntn-1 resulted in decreased activity of the PI3K/Akt signaling and docetaxel resistance in PCa cells lines and xenografts [ 44 ]. Since Pten loss and PI3K/AKT dysregulation are strongly associated with advanced PCa and CRPC, this preclinical finding draws attention to the potential collaborative role between EMT and common PCa driver mutations.…”

“…As discussed above, many EMT drivers are epigenetically regulated, so drugs that influence DNA methylation, histone modification, and plasticity are emerging as potential therapeutic targets for overcoming EMT [ 95 ]. In PCa, EMT appears to be an important mediator of acquired resistance to both androgen deprivation and docetaxel therapies [ 44 , 61 , 72 ].…”

Zhoushi Qi Ling decoction represses docetaxel resistance and glycolysis of castration-resistant prostate cancer via regulation of SNHG10/miR-1271-5p/TRIM66 axis

“…The cells were maintained in RPMI-1640 medium (Gibco, Grand Island, NY) containing 10% fetal bovine serum (Gibco) and 1% penicillin/streptomycin (Gibco) at 37°C with 5% CO 2 . Docetaxel-resistant (DR) cell lines (PC3-DR and DU145-DR) were successfully established via exposing monolayer-cultured cells to incremental concentrations of docetaxel (dissolved in DMSO; Sigma, St. Louis, MO, USA) in scheduled procedures according to the methods described previously [ 18 , 19 ]. The established DR cells were regularly cultured in the medium containing docetaxel (10 nM).…”

Contactin 1: An Important and Emerging Oncogenic Protein Promoting Cancer Progression and Metastasis

“…CNTN1 inhibition also increased expression of E-cadherin while reduced N-cadherin and Vimentin, suggesting an inhibition of the EMT process pivotal in cancer metastases ( Figure 4 ). Furthermore, docetaxel (Dox)-resistant PC cells exhibited upregulated CNTN1 expression and an EMT phenotype compared to parental cells [ 73 ]. Silencing of CNTN1 with short hairpin RNA (shRNA) inhibited cellular malignant phenotype and reduced expression of pluripotent markers such as CD44, octamer-binding transcription factor 4 (OCT-4), and Nanog.…”