Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor gamma Activation

摘要

Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantia L.) has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3beta,7beta-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR) y activation. Luciferase reporter assays indicated the ability of DMC to activate PPARy, and pharmacological inhibition of PPARy protected cells from DMC s antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARgamma-targeted signaling effectors, including cyclin Dl, CDK6, Bd-2, XIAP, cydooxygenase-2, NF-kB, and estrogen receptor alpha, and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK) B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPARy-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.