Theranostics 2020; 10(15):6928-6945. doi:10.7150/thno.43811 This issue Cite

Research Paper

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

Huizhen Sun1*, Husheng Wang1*, Xue Wang1*, Yoichi Aoki2, Xinjing Wang1, Yufei Yang3, Xi Cheng3, Ziliang Wang1✉, Xipeng Wang1✉

1. Department of Gynecology and Obstetrics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
2. Department of Gynecologic Oncology, Cancer Institute Hospital, Tokyo, Japan.
3. Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
*These authors contributed equally to this work.

Citation:
Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, Cheng X, Wang Z, Wang X. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics 2020; 10(15):6928-6945. doi:10.7150/thno.43811. https://www.thno.org/v10p6928.htm
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Abstract

Graphic abstract

Rationale: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Aurora-A, SOX8, PDOs, Chemoresistance, Ovarian cancer


Citation styles

APA
Sun, H., Wang, H., Wang, X., Aoki, Y., Wang, X., Yang, Y., Cheng, X., Wang, Z., Wang, X. (2020). Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics, 10(15), 6928-6945. https://doi.org/10.7150/thno.43811.

ACS
Sun, H.; Wang, H.; Wang, X.; Aoki, Y.; Wang, X.; Yang, Y.; Cheng, X.; Wang, Z.; Wang, X. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics 2020, 10 (15), 6928-6945. DOI: 10.7150/thno.43811.

NLM
Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, Cheng X, Wang Z, Wang X. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics 2020; 10(15):6928-6945. doi:10.7150/thno.43811. https://www.thno.org/v10p6928.htm

CSE
Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, Cheng X, Wang Z, Wang X. 2020. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics. 10(15):6928-6945.

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