EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling

Abstract

Docetaxel-based chemotherapy is a standard-of-care treatment for metastatic prostate cancer (PCa), and chemoresistance remains a major challenge in clinical practice. Recent studies have demonstrated that circular RNAs (circRNAs) play critical roles in the development and progression of PCa. However, the biological roles and potential functions of circRNAs in mediating docetaxel-resistant PCa have yet to be well elucidated. In this study, we analyzed the expression profiles of circRNAs in docetaxel-resistant and -sensitive PCa cells through RNA sequencing and found that expression of circARHGAP29 was significantly upregulated in docetaxel-resistant cell lines and clinical samples. Ectopic expression of circARHGAP29 triggered docetaxel resistance and aerobic glycolysis in PCa cells, which was reduced by silencing circARHGAP29. Moreover, eukaryotic initiation factor 4A3 (EIF4A3), which bound the back-spliced junction site and the downstream flanking sequence of circARHGAP29, induced cyclization and cytoplasmic export of circARHGAP29. circARHGAP29 increased the stability of lactate dehydrogenase A (LDHA) mRNA by strengthening its interaction with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), leading to enhanced glycolytic metabolism. In addition, circARHGAP29 interacted with and stabilized c-Myc mRNA and protein, which further increased LDHA expression by facilitating its transcription. These findings reveal the crucial function of circARHGAP29 in PCa glycolysis by increasing and stabilizing LDHA mRNA, providing a promising therapeutic target in docetaxel-resistant PCa. SignificanceUpregulation of a novel circRNA, circARHGAP29, promotes docetaxel resistance and glycolytic metabolism, suggesting it could be a prognostic biomarker and therapeutic target in chemoresistant prostate cancer.Research.

TFAP2C-Mediated lncRNA PCAT1 Inhibits Ferroptosis in Docetaxel-Resistant Prostate Cancer Through c-Myc/miR-25-3p/SLC7A11 Signaling

“…To clarify whether ferroptosis inducer can also inhibit DTX-resistant PCa, we generated two acquired DTX-resistant cell lines (PC3/DR and 22RV1/DR) derived from castration-resistant PCa cells (PC3 and 22RV1) as our previously described ( 19 , 20 ). DTX resistance was further validated by cell viability and colony formation assays ( Figure S1A–D ).…”

“…The human prostate carcinoma cell lines PC3 and 22RV1 were purchased from the National Collection of Authenticated Cell Culture (Shanghai, China) and maintained in DMEM/F12 medium supplemented with 10% fetal bovine serum (Biological Industries, Israel) and 1% antibiotics (penicillin and streptomycin, HyClone, USA). As previously described, DTX-resistant cell lines (PC3/DR and 22RV1/DR) were developed by stepwise increased DTX concentrations over a period of 8-9 months ( 19 , 20 ). DTX, Erastin, Ferrostatin-1 (Fer-1),CHX and Borz were purchased from MedChemExpress (China).…”

“…PC3 and PC3/DR cells (5×10 6 cells) were subcutaneously injected into each flank of six-week-old male BALB/c nude mice (HFK Biotech, China). When the tumor volume reached 100 mm 3 , the mice were treated with Dimethyl Sulfoxide (DMSO) alone, DTX (5 mg/kg body weight, every two days) with DMSO or erastin (20 mg/kg body weight in 20 μl DMSO plus 130 μl corn oil, daily) by intraperitoneal injection, as previously described ( 9 , 20 ). The tumor volumes of the mice were assessed by measuring the length and width every three days.…”

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

“…Increasing evidence shows that aerobic glycolysis is an apparent characteristic of energy metabolism in cancer cells, and an increase in glycolysis is beneficial for tumour progression and recurrence, especially chemoresistance of cancer cells. 9 , 27 , 28 Jia et al reported that activation of glycolysis improves tumor malignancy and chemoresistance of hepatocellular carcinoma. 29 And the study of Lin et al found that POU2F1 directly bound to the ALDOA promoter and then decreased the sensitivity to oxaliplatin in colon cancer cells by enhancing glycolysis.…”

LncRNAs and CircRNAs in cancer

“… 31 CircRNA participated in some important diseases progress control, and they are also regarded as novel biomarkers in cancer development, progression, and drug resistance. 32 CircRNAs have been reported to be associated with different types of cancers, including lung cancer, 33 prostate cancer, 34 and melanoma. 35 CircRNAs also have numerous mechanisms in cancer.…”