Lysophosphatidic acid suppresses apoptosis of high-grade serous ovarian cancer cells by inducing autophagy activity and promotes cell-cycle progression via EGFR-PI3K/Aurora-AThr288-geminin dual signaling pathways

Haile Zhao; Peijun Jia; Kathleen Nanding; Man Wu; Xiaozhou Bai; Morigen Morigen; Lifei Fan

doi:10.3389/fphar.2022.1046269

Lysophosphatidic acid suppresses apoptosis of high-grade serous ovarian cancer cells by inducing autophagy activity and promotes cell-cycle progression via EGFR-PI3K/Aurora-A^Thr288-geminin dual signaling pathways

Front Pharmacol. 2022 Dec 19:13:1046269. doi: 10.3389/fphar.2022.1046269. eCollection 2022.

Authors

Haile Zhao¹, Peijun Jia¹, Kathleen Nanding¹, Man Wu¹, Xiaozhou Bai¹, Morigen Morigen¹, Lifei Fan¹

Affiliation

¹ Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, China.

Abstract

Lysophosphatidic acid (LPA) and geminin are overexpressed in ovarian cancer, and increasing evidence supports their contribution to ovarian tumor development. Here, we reveal that geminin depletion induces autophagy suppression and enhances reactive oxygen species (ROS) production and apoptosis of high-grade serous ovarian cancer (HGSOC) cells. Bioinformatics analysis and pharmacological inhibition studies confirm that LPA activates geminin expression in the early S phase in HGSOC cells via the LPAR_1/3/MMPs/EGFR/PI3K/mTOR pathway. Furthermore, LPA phosphorylates Aurora-A kinase on Thr288 through EGFR transactivation, and this event potentiates additional geminin stabilization. In turn, overexpressed and stabilized geminin regulates DNA replication, cell-cycle progression, and cell proliferation of HGSOC cells. Our data provide potential targets for enhancing the clinical benefit of HGSOC precision medicine.

Keywords: Aurora-AThr288; EGFR transactivation; LPA; apoptosis; autophagy; geminin.