ER-Mitochondria Calcium Flux by β-Sitosterol Promotes Cell Death in Ovarian Cancer

Abstract

Phytosterols, which are derived from plants, have various beneficial physiological effects, including anti-hypercholesterolemic, anti-inflammatory, and antifungal activities. The anticancer activities of natural products have attracted great attention, being associated with a low risk of side effects and not inducing antineoplastic resistance. β-sitosterol, a phytosterol, has been reported to have anticancer effects against fibrosarcoma and colon, breast, lung, and prostate cancer. However, there are no reports of its activity against ovarian cancer. Therefore, we investigated whether β-sitosterol shows anticancer effects against ovarian cancer using human ovarian cancer cell lines. We confirmed that β-sitosterol induced the apoptosis of ovarian cancer cells and suppressed their proliferation. It triggered pro-apoptosis signals and the loss of mitochondrial membrane potential, enhanced the generation of reactive oxygen species and calcium influx through the endoplasmic reticulum–mitochondria axis, and altered signaling pathways in human ovarian cancer cells. In addition, we observed inhibition of cell aggregation, suppression of cell growth, and decreased cell migration in ovarian cancer cells treated with β-sitosterol. Further, our data obtained using ovarian cancer cells showed that, in combination with standard anti-cancer drugs, β-sitosterol demonstrated synergistic anti-cancer effects. Thus, our study suggests that β-sitosterol may exert anti-cancer effects against ovarian cancer in humans.

Phytosterol intake and overall survival in newly diagnosed ovarian cancer patients: An ambispective cohort study

“…Vitro experiments have shown that several phytosterols, including campesterol, β-sitosterol, and stigmasterol, exerted anticancer effect on OC, which provided potential biological mechanisms for our findings. These phytosterols activated proapoptotic signals and induced the apoptosis of OC cells, simultaneously upregulated the calcium levels of cytosolic and mitochondrial and caused excessive calcium overload (34)(35)(36), which further promoted the cell apoptosis (37,38). Besides, these phytosterols promoted the overexpression of unfolded protein response and endoplasmic reticulum-mitochondria axis signals, which triggered cell apoptosis pathway and autophagic stimulus and caused endoplasmic reticulum stress (34)(35)(36)39), the accumulation of endoplasmic reticulum stress induced the cancer cells death (40).…”

Molecular Mechanism of β-Sitosterol and its Derivatives in Tumor Progression

“…Similarly, SIT stimulated apoptosis in breast cancer MDA-MB-231 cells by increasing the Bax/Bcl-2 ratio and promoting mitochondrial membrane depolarization ( 27 ). Further, SIT elevated the expression level of Bax, Bcl-2 antagonist/killer (Bak), caspase-3 and -9, and cytochrome C in ovarian cancer cells (ES2 and OV90) in a dose-dependent manner ( 28 ). This data indicates that SIT upregulates pro-apoptotic signals in ovarian cancer cells.…”

“…In another study, Bae et al. pretreated cells with N-acetylcysteine (NAC) for 1 h before SIT treatment to assess the relationship between SIT-induced mitochondrial dysfunction and ROS production ( 28 ). The results showed that NAC could partially inhibit SIT-induced loss of mitochondrial membrane potential (MMP) in ovarian cancer cells (OV90), suggesting that SIT mainly exerted adverse effects on mitochondria and indirectly disrupted ROS homeostasis.…”

“…treated human ovarian cancer cells (ES2 and OV90 cancer cells) with SIT alone or in combination with cisplatin or paclitaxel. SIT treatment could further enhance cisplatin- and paclitaxel-induced growth inhibition of cancer cells ( 28 ). Another study experimentally demonstrated that SIT combined with cyclophosphamide could effectively enhance anti-tumor effects ( 80 ).…”

“…Plant-derived phytosterols have various beneficial physiological effects, including anti-hypercholesterolemic, anti-inflammatory, and anti-fungal activity. Considerable attention has been paid to the anti-cancer activity of these natural products with a low risk of side effects and anti-tumor resistance ( 28 ). Unlike currently available cancer chemotherapeutics, phytosterols are generally considered safe for human consumption and can be widely added to food matrices.…”