title: Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells.
abstract: Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca(2+) concentration, including cytosolic and mitochondrial Ca(2+) in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca(2+) overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance.
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China; 2Department of Histology and Embryology, Jilin Medical University, Jilin 132013, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: 3Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: 3Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Shibing
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Li
authors.affiliation: 1Medical Research Laboratory, Jilin Medical University, Jilin 132013, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 2Department of Histology and Embryology, Jilin Medical University, Jilin 132013, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Li
keywords: calcium; cisplatin resistance; ovarian cancer; oxidative stress