title: 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 GADD45α in a p53-independent manner, and activates JNK/p38 MAPK signaling. Interestingly, Cu-I-induced GADD45α 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.
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: C
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: C
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Laboratory Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: X
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: G
authors.initials: G
authors.lastname: Duan
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: T
authors.initials: T
authors.lastname: Ling
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, Jiangsu Province, China.
authors.forename: X
authors.initials: X
authors.lastname: Zou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C038106:cucurbitacin I