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, Chuiwen; Zhang, B; Zhang, S; Duan, Chaoqin; Cao, Yue; Kang, Wei; Yan, Hongli; Ding, Xiaohui; Zhang, Fan; Wu, Lei; Duan, Gengli; Shen, Shanshan; Xu, Guohai; Zhang, W; Chen, M; Huang, Shenglan; Zhang, X; Lv, Ying; Ling, Thai-Yen; Wang, L; Zou, Xiaoping

doi:10.1038/cddis.2016.13

Cited by 42 publications

(39 citation statements)

References 39 publications

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“…7,8 As one of the 12 categories of cucurbitacins, cucurbitacin-I shows a potent anticancer effect on several types of cancer cells, including breast cancer, lung cancer, and glioma. [9][10][11][12][13] Cucurbitacin-I performs its anticancer action through the inhibition of JAK/ STAT3, PI3K/AKT/p70S6K, or PAK1/PAK4 signaling pathways, as well as the modulation of the balance between autophagic and apoptotic modes of cancer cell death. In fact, the molecular and cellular mechanisms underlying the induction of cucurbitacin-I in tumor cell death are very complex, which deserves further study.…”

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confidence: 99%

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Chen

et al. 2018

J of Cellular Biochemistry

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Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin‐I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin‐I. Here, we investigated the role of ERS in cucurbitacin‐I‐treated SKOV3 ovarian cancer cells and PANC‐1 pancreatic cancer cells. We confirmed that cucurbitacin‐I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R‐like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase‐12‐dependent ERS‐associated apoptosis, autophagy and autophagy flux levels and caspase‐independent nonapoptotic cell death. Furthermore, 4‐phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin‐I‐induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin‐I‐induced reactive oxygen species and Ca 2+. Our results suggested that cucurbitacin‐I‐induced cancer cell death through the excessive ERS and CHOP‐Bax and caspase‐12‐dependent ERS‐associated apoptosis, as well as ERS‐dependent autophagy, autophagy flux, and caspase‐independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.

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confidence: 99%

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Chen

et al. 2018

J of Cellular Biochemistry

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“…GADD45α is a well‐known p53‐responsive stress protein to repair DNA damage, induce G2/M cell cycle arrest and apoptosis in various cancer cells . Recently we have demonstrated that GADD45α can be induced by Cucurbitacin‐I through a p53‐independent manner and associated with G2/M cell cycle arrest and apoptosis in gastric cancer cells . Earlier studies have revealed that GADD45α was downregulated in HCC cells, and its ectopic expression led to G2/M arrest .…”

Section: Discussionmentioning

confidence: 99%

“…siRNAs target UBE2Q1 and GADD45α as well as a negative control siRNA (sequences are detailed in Supplementary Table S1) were purchased from Invitrogen (Carlsbad, CA). Transfection was carried out using Lipofectamine RNAiMax Reagent (Invitrogen) as described previously . Lentivirus plasmid vectors pLKO.1‐puro vectors containing shRNA targeting UBE2Q1 (TRCN0000004205) and pLKO.1‐puro lentiviral vector expressing a non‐targeting shRNA was used to establish the stable cell line.…”

Section: Methodsmentioning

confidence: 99%

“…40 Recently we have demonstrated that GADD45α can be induced by Cucurbitacin-I through a p53-independent manner and associated with G2/M cell cycle arrest and apoptosis in gastric cancer cells. 23 Earlier studies have revealed that GADD45α was downregulated in HCC cells, 41,42 and its ectopic expression led to G2/M arrest. 43 In contrary, our data revealed that induction of GADD45α following UBE2Q1 silence led to cellular apoptosis instead of G2/M arrest.…”

Section: Gene Silence Of Ube2q1 Inhibits β-Catenin-egfr-pi3k-akt-mtmentioning

confidence: 99%

“…Colony formation assay was carried out in a 6-well plate for 14 days; the colonies were fixed with methanol and stained with crystal violet. All experiments were carried out as previously described 23,24,26 and done in triplicate and repeated three independent times. Filamentous actins were stained with TRITC-labeled Phalloidin (5 ug/mL) for 2 h at room temperature.…”

Section: Cell Viability Proliferation and Colony Formation Assaymentioning

confidence: 99%

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Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β‐catenin‐EGFR‐PI3K‐Akt‐mTOR signaling pathway

Zhang

Deng

Wang

et al. 2017

Molecular Carcinogenesis

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer and represents a highly malignant tumor with a poor prognosis. Therapeutic modalities for HCC are limited and generally ineffective. UBE2Q1 is a putative E2 ubiquitin conjugating enzyme, and has been shown to be overexpressed in various types of cancers including HCC. How UBE2Q1 contributes to hepatocarcinogenesis remains unknown. Here, we show that UBE2Q1 is up-regulated in HCC cell lines and in a subset of human HCC tissues. Up-regulation of UBE2Q1 in primary HCC tumors was significantly correlated with shorter overall survival and disease-free survival. Mechanistically, we showed that the frequent up-regulation of UBE2Q1 in HCCs was attributed to the recurrent UBE2Q1 gene copy gain at chromosome 1q21. Functionally, we showed that knockdown of UBE2Q1 reduced HCC cell proliferation, promoted apoptosis via induction of GADD45α, and suppressed orthotopic tumorigenicity both in vitro and in vivo. Inactivation of UBE2Q1 also impeded HCC cell migration and invasion in vitro through regulating EMT process, and suppressed HCC metastasis in vivo. Interestingly, our data revealed a role of UBE2Q1 in the regulation of β-catenin-EGFR-PI3K-Akt-mTOR signaling pathway. Our findings indicate that UBE2Q1 is a candidate oncogene involved in HCC development and progression and therefore a potential therapeutic target in applicable HCC patients.

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LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

Jiang

Yang

et al. 2020

FEBS Open Bio

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Lemur tyrosine kinase 3 (LMTK3) is a key member of the serine–threonine tyrosine kinase family. It plays an important role in breast cancer tumorigenesis and progression. However, its biological role in bladder cancer remains elusive. In this study, we demonstrated that LMTK3 was overexpressed in bladder cancer and was positively correlated with bladder cancer malignancy. High LMTK3 expression predicted poor overall survival. Knockdown of LMTK3 in bladder cancer cells triggered cell‐cycle arrest at G2/M phase, suppressed cell growth, and induced cell apoptosis in bladder cancer cells. Furthermore, Transwell assays revealed that reduction of LMTK3 decreased cell migration by regulating the epithelial‐to‐mesenchymal transition pathway. Conversely, LKTM3 overexpression was shown to promote proliferation and migration of bladder cancer cells. We assessed phosphorylation of MEK and ERK1/2 in bladder cancer cells depleted of LMTK3 and demonstrated a reduced phosphorylation status compared with the control group. Using an MAPK signaling‐specific inhibitor, U0126, we could rescue the promotion of proliferation and viability in LMTK3‐overexpressing cells. In conclusion, we extend the status of LMTK3 as an oncogene in bladder cancer and provide evidence for its function via the activation of the ERK/MAPK pathway. Thus, targeting LMTK3 may hold potential as a diagnostic and prognostic biomarker and as a possible future treatment for bladder cancer.

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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

Cited by 42 publications

References 39 publications

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway

Upregulation of UBE2Q1 via gene copy number gain in hepatocellular carcinoma promotes cancer progression through β‐catenin‐EGFR‐PI3K‐Akt‐mTOR signaling pathway

LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway

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