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ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer

Oncogene volume 41, pages 1114–1128 (2022)Cite this article

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Abstract

Platinum resistance accounts for much of the high mortality and morbidity associated with ovarian cancer. Identification of targets with significant clinical translational potential remains an unmet challenge. Through a high-throughput synthetical lethal screening for clinically relevant targets using 290 kinase inhibitors, we identify calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) as a critical vulnerability in cisplatin-resistant ovarian cancer cells. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanistically, CAMK2G directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Thereby, CAMK2G facilitates the adaptive redox homeostasis upon cisplatin treatment and drives cisplatin resistance. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers. This study reveals a key kinase network consisting of CAMK2G and ITPKB for ROS sense and scavenging in ovarian cancer cells to maintain redox homeostasis, offering a potential strategy for cisplatin resistance treatment.

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Fig. 1: CAMKII inhibitor significantly sensitized cisplatin treatment in vitro and in vivo.
Fig. 2: CAMK2G activated by endogenous ROS contributes to cisplatin resistance in cisplatin-resistant ovarian cancer cells.
Fig. 3: CAMK2G activity further stimulated by cisplatin-induced ROS in a feedback manner in cisplatin-resistant ovarian cancer cells.
Fig. 4: CAMK2G bound and phosphorylated ITPKB at serine 174 to activate ITPKB in cisplatin-resistant ovarian cancer cells.
Fig. 5: S174 phosphorylation activates ITPKB by promoting calmodulin binding.
Fig. 6: CAMK2G signals through ITPKB phosphorylation to confer cisplatin resistance by curbing cisplatin-induced ROS stress in vitro and in vivo.
Fig. 7: Level of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in ovarian cancer cell lines.
Fig. 8: Activity of ROS-CAMK2G-pITPKB pathway in primary cancer samples correlates with cisplatin resistance in ovarian cancer patients.
Fig. 9: Proposed model for the ROS-controlled regulation of CAMK2G-ITPKB pathway and cisplatin resistance in ovarian cancer.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China 82003194 (CP) and 82073074 (BL), Guangdong Basic and Applied Basic Research Foundation 2021A1515012446 (CP), Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation 2020B1212060018 (CP), and 2019 AACR Anna D. Barker Basic Cancer Research Fellowship (CP).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Jie Li, Chunyu Zhang, Hua Huang & Shuzhong Yao

  2. Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Cuimiao Zheng, Mingshuo Wang, Qingyuan Dai, Qing Yang, Xianzhi Yang, Jingyi Lu, Wenfeng Pan, Bo Li & Chaoyun Pan

  3. Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Cuimiao Zheng, Bo Li & Chaoyun Pan

  4. Department of Microbiology and Molecular Genetics, Duke University School of Medicine, Durham, NC, 27708, USA

    Anna D. Umano

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  1. Jie Li
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Contributions

JL: experimental design, data acquisition, data analysis, manuscript writing. CZ, MW, QD, QY, XY, JL, WP: experimental methods, data acquisition. CZh, HH: key reagents. AU: manuscript editing. SY, BL: data analysis, funding. CP: funding, supervision, experimental design, data analysis, manuscript writing.

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Correspondence to Chaoyun Pan.

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Li, J., Zheng, C., Wang, M. et al. ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer. Oncogene 41, 1114–1128 (2022). https://doi.org/10.1038/s41388-021-02149-x

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