INPP4B reverses docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer.
Docetaxel efficiency in the therapy of prostate cancer (PCa) patients is limited due to the development of chemoresistance. Recent studies have implied a role of INPP4B in tumor chemoresistance, while the effects of INPP4B on docetaxel resistance in PCa have not been elucidated. In the present study, the docetaxel-resistant human PCa cell lines PC3-DR and DU-145-DR were established from the parental cell lines PC3 and DU-145, and the expression and role of INPP4B in docetaxel-resistant PCa cells were investigated. The results demonstrated that INPP4B expression was significantly downregulated in docetaxel-resistant cells. Overexpression of INPP4B increased the sensitivity to docetaxel and promoted cell apoptosis in PC3-DR and DU-145-DR cells. In addition, INPP4B overexpression downregulated the expression of the mesenchymal markers fibronectin, N-cadherin, and vimentin, and upregulated the expression level of the epithelial maker E-cadherin. Furthermore, INPP4B overexpression markedly inhibited the PI3K/Akt pathway. We also found that IGF-1, the inhibitor of PI3K/Akt, markedly blocked the change in EMT markers induced by overexpression of INPP4B, and reversed the resistance of PC3-DR and DU-145-DR cells to docetaxel, which is sensitized by Flag-INPP4B. In summary, the presented data indicate that INPP4B is crucial for docetaxel-resistant PCa cell survival, potentially by regulating EMT through the PI3K/Akt signaling pathway.
Department of Urology, The Second Affiliated Hospital of Xi'an Jiao Tong University, PR China.
Haiwen
H
Chen
Department of Urology, The Second Affiliated Hospital of Xi'an Jiao Tong University, PR China. Electronic address: honglianglity@sina.com.
Hongliang
H
Li
Department of Urology, The Second Affiliated Hospital of Xi'an Jiao Tong University, PR China.
Qi
Q
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077143:Docetaxel; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
Docetaxel; Epithelial-mesenchymal transition; INPP4B; PI3K/Akt; Prostate cancer