TY - JOUR
T1 - Cucurbitane triterpenoid from momordica charantia induces apoptosis and autophagy in breast cancer cells, in part, through peroxisome proliferator-activated receptor γ activation
AU - Weng, Jing Ru
AU - Bai, Li Yuan
AU - Chiu, Chang Fang
AU - Hu, Jing Lan
AU - Chiu, Shih Jiuan
AU - Wu, Chia Yung
PY - 2013
Y1 - 2013
N2 - 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 3β,7β- 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 PPARγ, and pharmacological inhibition of PPARγ protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARγ-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-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 PPARγ-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.
AB - 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 3β,7β- 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 PPARγ, and pharmacological inhibition of PPARγ protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARγ-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-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 PPARγ-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.
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U2 - 10.1155/2013/935675
DO - 10.1155/2013/935675
M3 - Article
C2 - 23843889
AN - SCOPUS:84880170193
SN - 1741-427X
VL - 2013
JO - Evidence-based Complementary and Alternative Medicine
JF - Evidence-based Complementary and Alternative Medicine
M1 - 935675
ER -