Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells

• Published in: Theranostics 2020-01, Vol.10 (15), p.6928-6945
• Main Authors: Sun, Huizhen, Wang, Husheng, Wang, Xue, Aoki, Yoichi, Wang, Xinjing, Yang, Yufei, Cheng, Xi, Wang, Ziliang, Wang, Xipeng
• Format: Article
• Language: English
• Subjects: Animal research; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Aurora Kinase A - genetics; Aurora Kinase A - metabolism; Cancer therapies; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Cisplatin - pharmacology; Drug Resistance, Neoplasm; Experiments; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation, Neoplastic; Glucose; Glucose - metabolism; Humans; Kinases; Medical prognosis; Metabolism; Metabolites; Mice, Inbred BALB C; Mice, Nude; Organoids; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Patients; Research Paper; Senescence; Signal Transduction; SOXE Transcription Factors - genetics; SOXE Transcription Factors - metabolism; Transcription factors; Xenograft Model Antitumor Assays
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.43811

Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present. RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer. Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression. Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.