Abstract
Ovarian cancer presents the highest mortality rate among gynecological tumors. Here, we measured cell viability, proliferation, apoptosis, autophagy, and expression of endoplasmic reticulum stress (ERS)-related proteins, PI3K/AKT/mTOR pathway-related proteins, and apoptosis- and autophagy-related proteins in SKOV3 and SKOV3/CDDP cells treated with combinations of CDDP, tunicamycin, and BEZ235 (blank control, CDDP, CDDP + tunicamycin, CDDP + BEZ235, and CDDP + tunicamycin + BEZ235). Increasing concentrations of tunicamycin and CDDP activated ERS in SKOV3 cells, reduced cell viability and proliferation, increased apoptosis and autophagy, enhanced expression of ERS-related proteins, and inhibited expression of PI3K/AKT/mTOR pathway-related proteins. CDDP, tunicamycin, and BEZ235 acted synergistically to enhance these effects. We also detected lower expression of the ERS-related proteins caspase-3, LC3 II and Beclin 1 in ovarian cancer tissues than adjacent normal tissues. By contrast, expression of Bcl-2 and PI3K/AKT/mTOR pathway-related proteins was higher in ovarian cancer tissues than adjacent normal tissues. Lastly, expression of the ERS-related proteins Beclin 1, caspase-3 and LC3 II was higher in the sensitive group than the resistant group, while expression of Bcl-2, LC3 I, P62 and PI3K/AKT/mTOR pathway-related proteins was decreased. These results show that ERS promotes cell autophagy and apoptosis while reversing chemoresistance in ovarian cancer cells by inhibiting activation of the PI3K/AKT/mTOR signaling pathway.
Highlights
Ovarian cancer is one of the most common cancers in women and is the leading cause of death from gynecologic malignancies [1]
We found that tunicamycin inhibited the growth of SKOV3 cells in a concentration-dependent manner (Figure 1B)
Cell vitality reached 50% at 1 mg/L tunicamycin for 24 h. We used such concentration and incubation time in experiments testing for the effects of CDDP and BEZ235 on endoplasmic reticulum stress (ERS), the PI3K/AKT/Mammalian target of rapamycin (mTOR) signaling pathway, autophagy, proliferation and apoptosis
Summary
Ovarian cancer is one of the most common cancers in women and is the leading cause of death from gynecologic malignancies [1]. Due to the subtlety of symptoms in its early stages, ~75% of women are diagnosed with advanced disease at initial diagnosis [1]. The currently recommended management is primary cytoreductive surgery followed by platinum-paclitaxel combination chemotherapy [2]. Cell apoptosis and autophagy trigger the unfolded protein response, which can result in physiological or molecular disturbances that activate ER Stress (ERS) [4, 5]. ERS can activate autophagy while autophagy inhibition can enhance ERS-induced cell death [7]. Since ERS enhances tumor cell apoptosis, ERS activation could be exploited for therapeutic benefit against cancer [8]
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