Coumestrol Inhibits Proliferation and Migration of Prostate Cancer Cells by Regulating AKT, ERK1/2, and JNK MAPK Cell Signaling Cascades

Abstract

Coumestrol is the one of the major phytoestrogens which is abundant in soybeans, legumes, brussel sprouts, and spinach. The beneficial effects of coumestrol are well known in various biological processes including; neuroprotective effects on the nervous system, function of the female reproductive system, anti-bacterial properties, and anti-cancer effects. Although the anti-tumor activity of coumestrol has been demonstrated for ovarian, breast, lung, and cervical cancers, little is known of its effects on prostate cancer. Therefore, in the present study, we investigated the chemotherapeutic effects of coumestrol on two prostate cancer cell lines, PC3 and LNCaP. Our results showed that coumestrol decreased proliferation and migration and induced apoptosis in both PC3 and LNCaP cells. Moreover, effects of coumestrol on cell signaling pathways were investigated and it increased phosphorylation of ERK1/2, JNK, P90RSK, and P53 proteins in a dose- and time-dependent manner whereas phosphorylation of AKT was reduced by coumestrol under the same conditions for culture of PC3 and LNCaP cells. In addition, mitochondrial dysfunction was induced by coumestrol as evidenced by a significant loss of mitochondrial membrane potential. Furthermore, cleavage of caspase-3 and caspase-9, the apoptotic proteins associated with mitochondria, also changed in response to coumestrol. Coumestrol also caused mitochondrial dysfunction resulting in an increase in ROS production in PC3 and LNCaP cells. These results suggest that coumestrol can inhibit progression of prostate cancer and may be a novel chemotherapeutic agent for treatment of prostate cancer via effects mediated via the PI3K/AKT and ERK1/2 and JNK MAPK cell signaling pathways. J. Cell. Physiol. 232: 862-871, 2017. © 2016 Wiley Periodicals, Inc.

Tetramethylpyrazine regulates breast cancer cell viability, migration, invasion and apoptosis by affecting the activity of Akt and caspase-3

“…The Akt signaling pathway principally regulates the activity of cancer cells (30,31). Previous studies have indicated that the Akt signaling pathway is a key factor in the viability and migration of a number of types of tumor including colorectal (32), and prostate cancer (33), and glioblastoma (34) and osteosarcoma (35). Additionally, the Akt signaling pathway is an important regulator of breast cancer (36)(37)(38).…”

Chrysin induces death of prostate cancer cells by inducing ROS and ER stress

“…These agents include natural compounds derived from plants, vegetables, and fruits that are widely used due to minimum of side effects compared to traditional medicines and as an alternative strategy for treatment of cancers resistance to classical therapeutic agents (Grayson, ). We reported previously that coumestrol, a phytoestrogen found in soy products, suppresses phosphorylation of AKT in a dose‐ and time‐dependent manner (Lim, Jeong, Bazer, & Song, ). In addition, inhibition of the PI3K/AKT pathway using a pharmacological inhibitor, LY294002, enhanced inhibition of proliferation of PC‐3 and LNCaP cells.…”

Bioactive food and exercise in chronic kidney disease: Targeting the mitochondria

“…Coumestrol is a polyphenol with oestrogen properties found in raw clover sprouts, red clover, alfaalfa, soybeans, legumes, Brussel sprouts and spinach. This bioactive compound might elicit anticancer effects by affecting viability and mitochondrial functions and provoking apoptosis by inhibition of PI3K/AKT and activation of MAPKs (ERK1/2 and JNK) . Interestingly, coumestrol has been shown to activate SIRT‐1 and thereby initiating MB in cultured mouse skeletal muscle cells .…”

“…This bioactive compound might elicit anticancer effects by affecting viability and mitochondrial functions and provoking apoptosis by inhibition of PI3K/AKT and activation of MAPKs (ERK1/ 2 and JNK). 80 Interestingly, coumestrol has been shown to activate SIRT-1 and thereby initiating MB in cultured mouse skeletal muscle cells. 81 Using human placental choriocarcinoma cells, it was recently shown that coumestrol induces apoptotic effects on these cells by regulating cell signalling and mitochondrial-mediated functions mainly by stimulating ROS production.…”