Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death

Mott, Justin L.; Gores, Gregory J.

doi:10.1002/hep.21812

Cited by 32 publications

(20 citation statements)

References 70 publications

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“…Some physiologic proapoptotic molecules are down-regulated or inactivated in HCC, but the balance between death and survival is mainly broken due to overactivation of antiapoptotic signals (17,18). Therefore, liver cancer cells might show stronger requirements of these intracellular pathways to survive.…”

Section: Discussionmentioning

confidence: 99%

Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Caja¹,

Sancho²,

Bertrán³

et al. 2009

Cancer Research

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Transforming growth factor-B (TGF-B) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-B in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-B-induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-B-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-B, sensitizes them to cell death through a mitochondrialdependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-B and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-B-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.

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Section: Discussionmentioning

confidence: 99%

Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Caja¹,

Sancho²,

Bertrán³

et al. 2009

Cancer Research

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“…B-cell lymphoma 2 (Bcl-2) is a major anti-apoptotic signaling protein affecting the development of many different neoplasms, including hepatocellular cancer (28). For that, we next assessed Bcl-2 levels in the serum of mice using ELISA.…”

Section: Effects Of Wnt-1 Depletion On Selected Tumor Markersmentioning

confidence: 99%

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

et al. 2017

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Abstract. Recent evidence has suggested that downregulation of the Wnt/β-catenin signaling pathway may contribute to the development and growth of HCC. Consequently, elements of this pathway have begun to emerge as potential targets for improving outcomes of anti-HCC. Thus, the present study sought to examine the effects of Wnt-1 blockade using the classical diethylnitrosamine (DEN)-induced chemical carcinogenesis mouse model of HCC. The depletion of Wnt-1 using neutralizing antisera was done for ten consecutive days at the age of 9 months and mice were examined for the following 20 days. At that time, DEN-treated mice had multiple variably-sized hepatic cell adenomas. Anti-Wnt-1 was particularly potent in suppressing the expression of critical elements of the Wnt/β-catenin signaling pathway, such as β-catenin and Frizzled-1 receptor, however, not Dickkopf-related protein 1. This effect co-existed with the suppression of Cyclin D1, FOXM1, NF-κΒ and c-Jun commensurate with proliferation and apoptosis blockade in hepatocellular adenomas, and reduced Bcl-2 and c-Met in the serum of mice. Nonetheless, tumor size and multiplicity were found to be unaffected, suggesting that apoptosis may be equally important to proliferation in the context of counteracting DEN induced hepatocellular adenomas of mice.

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“…Some physiological proapoptotic molecules are downregulated or inactivated in HCC, but the balance between death and survival is mainly broken due to the over-activation of anti-apoptotic signals [4,10]. Among the de-regulated pathways that cause cells to replicate at a higher rate and/or results in cells avoiding apoptosis, is the EGFR pathway [11].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells

Caja

Sancho

Bertrán

et al. 2011

Journal of Hepatology

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Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death

Cited by 32 publications

References 70 publications

Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Overactivation of the MEK/ERK Pathway in Liver Tumor Cells Confers Resistance to TGF-β–Induced Cell Death through Impairing Up-regulation of the NADPH Oxidase NOX4

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells

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