Ezetimibe inhibits triple-negative breast cancer proliferation and promotes cell cycle arrest by targeting the PDGFR/AKT pathway

Qinyu He; Lingkai Kong; Weiwei Shi; Ding Ma; Kua Liu; Shuwei Yang; Qilei Xin; Chunping Jiang; Junhua Wu

doi:10.1016/j.heliyon.2023.e21343

Ezetimibe inhibits triple-negative breast cancer proliferation and promotes cell cycle arrest by targeting the PDGFR/AKT pathway

Heliyon. 2023 Oct 29;9(11):e21343. doi: 10.1016/j.heliyon.2023.e21343. eCollection 2023 Nov.

Authors

Qinyu He¹, Lingkai Kong¹, Weiwei Shi¹, Ding Ma^{1

2}, Kua Liu¹, Shuwei Yang¹, Qilei Xin³, Chunping Jiang^{3

1}, Junhua Wu^{3

1}

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Medical School, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu, 210093 China.
² Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Jinan Microecological Biomedicine Shandong Laboratory, Shounuo City Light West Block, Qingdao Road 3716#, Huaiyin District, Jinan City, Shandong Province, China.

Abstract

Cholesterol levels were strongly associated with tumor progression and metastasis. Targeted cholesterol metabolism has broad prospects in tumor treatment. Ezetimibe, the only FDA-approved inhibitor of cholesterol absorption, has been reported to be able to inhibit angiogenesis in liver cancer. However, the efficacy and specific mechanisms of Ezetimibe in the treatment of Triple-Negative Breast Cancer (TNBC)have not been reported. Our research shows Ezetimibe inhibits TNBC cell proliferation and blocks the cell cycle in the G1 phase. Mechanistically, Ezetimibe inhibits the activation of PDGFRβ/AKT pathway, thereby promoting cell cycle arrest and inhibiting cell proliferation. By overexpressing PDGFRβ in TNBC cells, we found that PDGFRβ significantly reduced the inhibitory effect of Ezetimibe on TNBC cell proliferation and the cell cycle. Similarly, SC79, an AKT agonist, can reduce the proliferation inhibitory and cycle-blocking effects of Ezetimibe on TNBC cells. Furthermore, the AKT inhibitor MK2206 enhanced the inhibitory effect of Ezetimibe on the cell cycle and proliferation ability of TNBC cells overexpressing PDGFRβ. In xenograft tumor models, we also found that Ezetimibe inhibited TNBC growth, an effect that can be blocked by overexpression of PDGFR or activation of AKT. In summary, we have demonstrated that EZ inhibits the PDGFR/AKT pathway, thereby halting TNBC cycle progression and tumor growth.

Keywords: Akt; Breast cancer; Cell cycle; Ezetimibe; PDGFRβ; Triple-negative breast cancer (TNBC).