JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand

Mucha, Simon; Rizzani, Antonia; Gerbes, Alexander L.; Čamaj, Peter; Thasler, Wolfgang E.; Bruns, Christiane; Eichhorst, Sören T.; Gallmeier, Eike; Kolligs, Frank T.; Göke, Burkhard; Toni, Enrico N. De

doi:10.1136/gut.2008.154625

Cited by 51 publications

(42 citation statements)

References 39 publications

(42 reference statements)

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“…8,26 On the one hand, Mucha et al 28 observed that JNK inhibition sensitizes hepatocellular carcinoma cells to TRAIL, but other groups have shown that JNK activation sensitizes hepatocellular carcinoma and breast cancer cells to TRAIL-induced apoptosis. 29,30 Our results would rather support the second conclusion because apoptosis induced by oxaliplatin/TRAIL combination was strongly suppressed by JNK inhibition or knockdown.…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

et al. 2011

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BACKGROUND & AIMS:Oxaliplatin sensitizes drug-resistant colon cancer cell lines to tumor necrosis factorrelated apoptosis inducing ligand (TRAIL), a death receptor ligand that is selective for cancer cells. We investigated the molecular mechanisms by which oxaliplatin sensitizes cancer cells to TRAIL-induced apoptosis. METHODS: We incubated the colon cancer cell lines HT29 and V9P, which are resistant to TRAIL, with TRAIL or with oxaliplatin for 2 hours, followed by TRAIL. Annexin V staining was used to measure apoptosis; RNA silencing and immunoblot experiments were used to study the roles of apoptosis-related proteins. Site-directed mutagenesis experiments were used to determine requirements for phosphorylation of Bcl-xL; coimmunoprecipitation experiments were used to analyze the interactions among Bcl-xL, Bax, and Bak, and activation of Bax. RESULTS: Oxaliplatin-induced sensitivity to TRAIL required activation of the mitochondrial apoptotic pathway; reduced expression of Bax, Bak, and caspase-9, and stable overexpression of Bcl-xL, reduced TRAIL-induced death of cells incubated with oxaliplatin. Mitochondrial priming was induced in cells that were sensitized by oxaliplatin and required signaling via c-Jun N-terminal kinase and phosphorylation of Bcl-xL. Mimicking constitutive phosphorylation of Bcl-xL by site-directed mutagenesis at serine 62 restored sensitivity of cells to TRAIL. Co-immunoprecipitation experiments showed that oxaliplatin-induced phosphorylation of Bcl-xL disrupted its ability to sequestrate Bax, allowing Bax to interact with Bak to induce TRAIL-mediated apoptosis. CONCLUSIONS: Oxaliplatin facilitates TRAIL-induced apoptosis in colon cancer cells by activating c-Jun N-terminal kinase signaling and phosphorylation of Bcl-xL. Oxaliplatin-induced sensitivity to TRAIL might be developed as an approach to cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

et al. 2011

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“…JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily, which also includes extracellular signal-regulated kinase (ERK) and the p38 family of kinases (2)(3)(4)(5). The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module.…”

Section: Introductionmentioning

confidence: 99%

“…The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module. MAPK kinase (MKK) 7 and MKK4 play a non-redundant role in the dual phosphorylation of JNK at Thr183 and Tyr185, which is required for JNK activity (2)(3)(4)(5). Once activated, JNK phosphorylates and activates c-Jun, a key component of the transcription factor activator protein-1 (AP-1) (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…MAPK kinase (MKK) 7 and MKK4 play a non-redundant role in the dual phosphorylation of JNK at Thr183 and Tyr185, which is required for JNK activity (2)(3)(4)(5). Once activated, JNK phosphorylates and activates c-Jun, a key component of the transcription factor activator protein-1 (AP-1) (2)(3)(4)(5). Elevated levels of JNK activity have been frequently observed in HCC and have been demonstrated to contribute to HCC growth by promoting cell proliferation and resistance to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

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RACK1 expression contributes to JNK activity, but JNK activity does not enhance RACK1 expression in hepatocellular carcinoma SMMC-7721 cells

Wang

Wen

et al. 2015

Oncology Letters

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Abstract.Receptor for activated C kinase 1 (RACK1) is up-regulated in hepatocellular carcinoma (HCC) and has been reported to augment c-Jun N-terminal protein kinase (JNK) activity in HCC SMMC-7721 cells. By contrast, activator protein-1, a downstream JNK transcription factor, has been revealed to mediate the overexpression of RACK1 in melanoma cells. Therefore, the association between RACK1 and JNK activity in HCC cells has yet to be completely elucidated. The present study analyzed the effects of RACK1 or JNK loss of function on the levels of RACK1 protein, JNK activity, cell proliferation and apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand in HCC SMMC-7721 cells. It was found that JNK loss of function exhibited no effect on RACK1 expression, whereas a loss of RACK1 function led to reduced JNK activity in SMMC-7721 cells. RACK1 and JNK loss of function resulted in the impaired oncogenic growth of SMMC-7721 cells. The present data further support a pivotal role of RACK1 in mediating enhanced JNK activity in HCC cells and also indicate that a novel mechanism exists for RACK1 overexpression in HCC SMMC-7721 cells. IntroductionHepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the human population, ranked the third most common cause of cancer-associated mortality worldwide, particularly in Africa and Asia (1). Although persistent viral infections and persistent exposure to hepatotoxic agents play a role in HCC neoplastic transformation (1), the underlying mechanism controlling the development and progression of HCC is largely unclear.Recently, c-Jun N-terminal protein kinase (JNK) has been reported to be involved in regulating liver tumorigenesis. JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily, which also includes extracellular signal-regulated kinase (ERK) and the p38 family of kinases (2-5). The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module. MAPK kinase (MKK) 7 and MKK4 play a non-redundant role in the dual phosphorylation of JNK at Thr183 and Tyr185, which is required for JNK activity (2-5). Once activated, JNK phosphorylates and activates c-Jun, a key component of the transcription factor activator protein-1 (AP-1) (2-5). Elevated levels of JNK activity have been frequently observed in HCC and have been demonstrated to contribute to HCC growth by promoting cell proliferation and resistance to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis (2-5).Receptor for activated C kinase 1 (RACK1), coded for by the GNB2L1 gene, is a scaffold protein with a propeller-like structure of seven WD40 repeats (6-10). Numerous studies have suggested that RACK1 plays a pivotal role in the coordination of cell growth, migration and differentiation during tumorigenesis (6-10). It has been demonstrated that RACK1 is up-regulated in HCC and that overexpressed RACK1 augments JNK activity, thereby promoting HCC growth by directly binding to MKK7 and enhancing MKK7 activity (11)....

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“…In addition, cancer stem cells induced c-Jun N-terminal kinase (JNK) and Wnt signaling interactions promoting their survival and proliferation in a model of colorectal carcinogenesis (18). In addition, Mucha et al (19) reported that JNK signaling was associated with TNF-related apoptosis-inducing ligand-induced cell death and resistance to apoptosis in HCC cells.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib inhibits cancer side population cells by targeting c-Jun N-terminal kinase signaling

Kim

Lee

Park

et al. 2012

Molecular Medicine Reports

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Abstract. Sorafenib is a systemic chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the anticancer effect of sorafenib in cancer stem cell-like cells, such as side population (SP) cells, in HCC and to analyze the signaling pathway for drug-resistance. To evaluate the anticancer effects of sorafenib, Huh7 and Huh-BAT cells were treated with sorafenib, fluorouracil (5-FU), and sorafenib plus 5-FU. These cells were examined for growth rates, the SP fraction, sphere-forming efficacy and expression of c-Jun N-terminal kinase (JNK) signaling molecules. Sorafenib and 5-FU treatment decreased growth rates in Huh7 and Huh-BAT cells; however, the treatments exerted different effects in SP cells and on the expression levels of JNK signaling molecules. Treatment with 5-FU increased the SP cell number and upregulated the expression of JNK signaling molecules. By contrast, sorafenib decreased the SP cell number and downregulated the expression of JNK signaling molecules. No significant differences in sphere-forming efficacy were observed subsequent to 5-FU and sorafenib treatment in Huh7 and Huh-BAT cells. These results indicate that sorafenib exerted anticancer effects in HCC and SP cells by targeting JNK signaling.

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JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand

Cited by 51 publications

References 39 publications

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

RACK1 expression contributes to JNK activity, but JNK activity does not enhance RACK1 expression in hepatocellular carcinoma SMMC-7721 cells

Sorafenib inhibits cancer side population cells by targeting c-Jun N-terminal kinase signaling

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