Lovastatin Treatment Inducing Apoptosis in Human Pancreatic Cancer Cells by Inhibiting Cholesterol Rafts in Plasma Membrane and Mitochondria

Author:

Gyoten Momoko1,Luo Yi12,Fujiwara-Tani Rina1,Mori Shiori1,Ogata Ruiko1,Kishi Shingo13,Kuniyasu Hiroki1ORCID

Affiliation:

1. Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan

2. Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China

3. Research Institute, Nozaki Tokushukai Hospital, 2-10-50 Tanigawa, Daito 574-0074, Osaka, Japan

Abstract

Resistance to anticancer drugs is a problem in the treatment of pancreatic ductal carcinoma (PDAC) and overcoming it is an important issue. Recently, it has been reported that statins induce apoptosis in cancer cells but the mechanism has not been completely elucidated. We investigated the antitumor mechanisms of statins against PDAC and their impact on resistance to gemcitabine (GEM). Lovastatin (LOVA) increased mitochondrial oxidative stress in PDAC cells, leading to apoptosis. LOVA reduced lipid rafts in the plasma membrane and mitochondria, suppressed the activation of epithelial growth factor receptor (EGFR) and AKT in plasma membrane rafts, and reduced B-cell lymphoma 2 (BCL2)-Bcl-2-associated X protein (BAX) binding and the translocation of F1F0 ATPase in mitochondrial rafts. In the three GEM-resistant cell lines derived from MIA and PANC1, the lipid rafts in the cell membrane and the mitochondria were increased to activate EGFR and AKT and to increase BCL2-BAX binding, which suppressed apoptosis. LOVA abrogated these anti-apoptotic effects by reducing the rafts in the resistant cells. By treating the resistant cells with LOVA, GEM sensitivity improved to the level of the parental cells. Therefore, cholesterol rafts contribute to drug resistance in PDAC. Further clinical research is warranted on overcoming anticancer drug resistance by statin-mediated intracellular cholesterol regulation.

Funder

MEXT KAKENHI

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference41 articles.

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