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 3 β ,7 β -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) γ activation.
Luciferase reporter assays indicated the ability of DMC to activate
PPAR γ , and pharmacological inhibition of
PPAR γ protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many
PPAR γ -targeted signaling effectors, including
cyclin D1, CDK6, Bcl-2, XIAP,
cyclooxygenase-2, NF- κ B, and
estrogen receptor α , 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
PPAR γ -targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.