2. Academic Validation
  3. Loss of RBPMS in ovarian cancer compromises the efficacy of EGFR inhibitor gefitinib through activating HER2/AKT/mTOR/P70S6K signaling

Loss of RBPMS in ovarian cancer compromises the efficacy of EGFR inhibitor gefitinib through activating HER2/AKT/mTOR/P70S6K signaling

  • Biochem Biophys Res Commun. 2022 Dec 31:637:348-357. doi: 10.1016/j.bbrc.2022.11.037.
Minzhen Li 1,  Meng Hu 2,  Yanyun Wang 3,  Zhili Xia 4,  Zhilong Li 3,  Juan Li 5,  Danxi Zheng 5,  Xuelian Zheng 3,  Mingrong Xi 6
Affiliations

Affiliations

  • 1 Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610000, China; Laboratory of Molecular and Translational Medicine, Sichuan University, Chengdu, 610000, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610000, China.
  • 3 Laboratory of Molecular and Translational Medicine, Sichuan University, Chengdu, 610000, China.
  • 4 The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China.
  • 5 Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610000, China; Laboratory of Molecular and Translational Medicine, Sichuan University, Chengdu, 610000, China.
  • 6 Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610000, China. Electronic address: [email protected].
PMID: 36423381 DOI: 10.1016/j.bbrc.2022.11.037
Abstract

RBPMS may be a tumor suppressor in Cancer, but its impact in modulation of drug sensitivity is unclear. This study aimed to investigate the regulatory role of RBPMS in cellular response to EGFR Inhibitor gefitinib in ovarian Cancer (OC). By western blotting assay, we revealed RBPMS was down-regulated in epithelial ovarian Cancer tissues compared to normal control ovarian epithelial tissues. Overexpression of RBPMS inhibited cell viability and proliferation, and conferred gefitinib sensitivity, accompanied by reduced expression of p-EGFR, and vice versa. Proteomic analysis and flow cytometry experiments showed that RBPMS induced S-stage cell cycle arrest in gefitinib-treated OC cells. Co-IP assay suggested that HER2 was a downstream target of RBPMS, and RBPMS negatively regulated HER2 expression. HER2 counteracted the stimulation of RBPMS to cell growth blocking, gefitinib sensitivity and cell cycle arrest. We further demonstrated that RBPMS overexpression suppressed the activation of p-AKT, p-mTOR and p-P70S6K, which was rescued by up-regulation of HER2. The combination of Akt Inhibitor MK2206 and gefitinib had a synergistic effect on OC cells with high level of RBPMS. In conclusion, through the direct inhibition of HER2/Akt/mTOR/p70S6K pathway, RBPMS may be a potential therapeutic target for improving gefitinib sensitivity in OC.

Keywords

AKT; Cell cycle; Gefitinib sensitivity; HER2; Ovarian cancer; RBPMS.

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