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Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo.

ABSTRACT: Cucurbitacin-I (Cu-I, also known as Elatericin B or JSI-124) is developed to inhibit constitutive and abnormal activation of STAT3 in many cancers, demonstrating a potent anticancer activity by targeting disruption of STAT3 function. Here, we for the first time systematically studied the underlying molecular mechanisms of Cu-I-induced gastric cancer cell death both in vitro and in vivo. In our study, we show that Cu-I markedly inhibits gastric cancer cell growth by inducing G2/M phase cell cycle arrest and apoptosis at low nanomolar concentrations via a STAT3-independent mechanism. Notably, Cu-I significantly decreases intracellular GSH/GSSG ratio by inhibiting NRF2 pathway to break cellular redox homeostasis, and subsequently induces the expression of GADD45? in a p53-independent manner, and activates JNK/p38 MAPK signaling. Interestingly, Cu-I-induced GADD45? and JNK/p38 MAPK signaling form a positive feedback loop and can be reciprocally regulated by each other. Therefore, the present study provides new insights into the mechanisms of antitumor effects of Cu-I, supporting Cu-I as an attractive therapeutic drug in gastric cancer by modulating the redox balance.

SUBMITTER: Deng C

PROVIDER: S-EPMC5399186 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo.

Deng C C Zhang B B Zhang S S Duan C C Cao Y Y Kang W W Yan H H Ding X X Zhou F F Wu L L Duan G G Shen S S Xu G G Zhang W W Chen M M Huang S S Zhang X X Lv Y Y Ling T T Wang L L Zou X X

Cell death & disease 20160218

Cucurbitacin-I (Cu-I, also known as Elatericin B or JSI-124) is developed to inhibit constitutive and abnormal activation of STAT3 in many cancers, demonstrating a potent anticancer activity by targeting disruption of STAT3 function. Here, we for the first time systematically studied the underlying molecular mechanisms of Cu-I-induced gastric cancer cell death both in vitro and in vivo. In our study, we show that Cu-I markedly inhibits gastric cancer cell growth by inducing G2/M phase cell cycle ...[more]

PMID: 26890145

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Dataset Information

Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo.

Publications

Low nanomolar concentrations of Cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo.

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