circCYP24A1 promotes Docetaxel resistance in prostate Cancer by Upregulating ALDH1A3

Abstract

Background Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. Methods circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients’ clinical and biological information. Results CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038–0.723; P = 0.017). Conclusions This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy.

MiR‐4524b‐5p‐targeting ALDH1A3 attenuates the proliferation and radioresistance of glioblastoma via PI3K/AKT/mTOR signaling

“… 35 Furthermore, abnormal expression of ALDH1A3 promotes chemotherapy resistance in prostate cancer, via the PI3K/AKT/mTOR axis. 36 Our study revealed a potential regulatory mechanism between ALDH1A3 and the PI3K/AKT/mTOR axis, which is consistent with previous studies. Reports have shown that malignant tumor cells utilize aerobic glycolysis to accumulate pyruvate, lactate, and glutathione, thus enhancing their antioxidant activity and resistance to the harmful effects of free radicals and oxidative stress resulting from radiotherapy.…”

“…It has been reported that ALDH1A3 activates the PI3K/AKT/mTOR signaling pathway by cross‐talking with the transcription factor PPARγ in pancreatic cancer 35 . Furthermore, abnormal expression of ALDH1A3 promotes chemotherapy resistance in prostate cancer, via the PI3K/AKT/mTOR axis 36 . Our study revealed a potential regulatory mechanism between ALDH1A3 and the PI3K/AKT/mTOR axis, which is consistent with previous studies.…”

circCYP24A1 facilitates esophageal squamous cell carcinoma progression through binding PKM2 to regulate NF-κB-induced CCL5 secretion

“…It is showed that circRNAs participated in tumor progression by activating multiple signal pathways such as β-catenin signaling [ 6 ], AMPK-mTOR pathway [ 8 ], TGF-β pathway [ 18 ], PI3K/AKT/mTOR signaling pathway [ 29 ]. To investigate the downstream signaling pathways involved in circCYP24A1, we performed mRNA expression profile microarray and found that circCYP24A1 was involved in regulation of cell proliferation and TNF signaling pathway.…”

“…To make clear the functional mechanism, the subcellular localization of circCYP24A1 in ESCC cells was detected and FISH revealed that most of circCYP24A1 localized in cytoplasm. CircRNAs located in the cytoplasm could acts as ceRNAs competitively bind miRNAs [ 18 , 29 , 30 ] and bind to RBPs [ 6 , 8 , 18 , 19 ]. A few cytoplasmic circRNAs also have the ability of translating novel polypeptides or proteins [ 16 , 38 , 39 ].…”

“…Ultimately, we identified a potential circRNA, termed circCYP24A1, which was up-regulated in ESCC tissues compared with those corresponding adjacent tissues. Recent studies have indicated that circCYP24A1 is abnormal expression in prostate cancer, renal cancer and cutaneous squamous cell carcinoma [29][30][31]. However, the clinical significance and functional mechanism of circCYP24A1 involved in the progression of ESCC remains obscure.…”