Targeting the JNK Signaling Pathway Potentiates the Antiproliferative Efficacy of Rapamycin in LS174T Colon Cancer Cells

Benoit, M; Dormond-Meuwly, Anne; Demartines, Nicolas; Dormond, Olivier

doi:10.1016/j.jss.2011.01.015

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…In both PEL cell lines, beside the induction of BiP, we found that proteasome inhibition by bortezomib determined a slight IRE1α upregulation (Figure 1A). Finally, JNK phosphorylation was analyzed, since IRE1 can activate, among other molecules, JNK that, in turn, may regulate cell survival [36]. We found JNK1/2 phosphorylation by bortezomib in both BC3 and BCBL1 cells (Figure 1A).…”

Section: Resultsmentioning

confidence: 95%

JNK and Macroautophagy Activation by Bortezomib Has a Pro-Survival Effect in Primary Effusion Lymphoma Cells

et al. 2013

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Understanding the mechanisms of autophagy induction and its role during chemotherapeutic treatments is of fundamental importance in order to manipulate it to improve the outcome of chemotherapy. In particular whether the bortezomib-induced autophagy plays a pro-survival or pro-death role is still controversial. In this study we investigated if bortezomib induced endoplasmic reticulum (ER) stress and activated autophagy in Primary Effusion Lymphoma (PEL) cells and how they influenced cell survival. We found that bortezomib induced up-regulation of the pro-survival and pro-death ER stress molecules BIP and CHOP and activated c-Jun NH2-terminal kinase (JNK), resulting in Bcl-2 phosphorylation and induction of autophagy. JNK and autophagy activation played a pro-survival role in this setting, thus their inhibition increased the bortezomib cytotoxic effect and PARP cleavage in PEL cells. Based on our results we suggest that the combination of bortezomib with JNK or autophagy inhibitors could be exploited to improve the outcome of therapy of this aggressive B cell lymphoma.

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Section: Resultsmentioning

confidence: 95%

JNK and Macroautophagy Activation by Bortezomib Has a Pro-Survival Effect in Primary Effusion Lymphoma Cells

et al. 2013

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“…Notably, rapalogs mediated eIF4E phosphorylation was dependent on Mnk (MAP kinase interacting kinase) and the inhibition of Mnk increased rapamycin-mediated growth inhibition [97]. Finally, it has also been reported that rapamycin-activated JNK signaling pathway in colon cancer cells plus combined JNK and mTOR inhibition had additive anti-tumor effects [99]. Future studies will explore the relevance of rapalogs mediated eIF4E or JNK activation in a clinical setting.…”

Section: Mtor and Cancer; What We Have Learned From Basic Researchmentioning

confidence: 99%

Targeting the Mammalian Target of Rapamycin (mTOR) in Cancer Therapy: Lessons from Past and Future Perspectives

Dufour

Dormond-Meuwly

Demartines

et al. 2011

Cancers

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Over the last decade, extensive studies have been made to understand the role played by the mammalian target of rapamycin (mTOR) in cancer. Knowledge in this field has been gained from discoveries in basic research as well as from observations made in patients treated with allosteric mTOR inhibitors such as rapamycin. Despite promising preclinical studies, targeting mTOR in cancer therapy has shown limited clinical benefits so far. However, recent findings have revealed the complexity of the functions of mTOR in cancer and have helped develop new strategies to improve the anticancer efficacy of mTOR inhibitors. In particular, a complex network between mTOR and other signaling pathways has been identified that influences the anticancer efficacy of mTOR inhibitors. In addition, an emerging role of mTOR in the tumor microenvironment has been suggested. In this review, we confront the major findings that have been made in the past, both in experimental settings as well as in clinical trials. We further review the strategies that have been designed to further improve the efficacy of therapies targeting mTOR.

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“…Numerous studies have documented that rapamycin may alter the activity of MAPKs including JNK, Erk1/2 and/or p38 under various conditions, thus affecting cell proliferation, survival and apoptosis (Benoit et al, 2011; Hahn et al, 2005; Huang et al, 2003; Kato et al, 2013; Kawasaki et al, 2010; Shi et al, 2005). Our previous studies have identified that Cd activates JNK, Erk1/2, and p38, but only JNK and Erk1/2 participate in Cd-induced apoptosis in neuronal cells (Chen et al, 2008b).…”

Section: Resultsmentioning

confidence: 99%

“…We have also revealed that Cd induction of ROS activates Erk1/2 and JNK pathways leading to apoptosis in neuronal cells (Chen et al, 2008a). However, of note, some data have documented that rapamycin affects the activity of JNK, Erk1/2 and p38 under different conditions (Benoit et al, 2011; Hahn et al, 2005; Huang et al, 2003; Kato et al, 2013; Kawasaki et al, 2010; Shi et al, 2005). This prompted us to ask whether and how rapamycin blocks Cd-induced mitochondrial ROS activation of JNK, Erk1/2 and p38 pathways, involved in rapamycin protection against Cd neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, treatment with rapamycin in vitro and in vivo prevented Cd induction of ROS-dependent neuronal cell apoptosis as well (Chen et al, 2011a; Chen et al, 2014b). Interestingly, emerging evidence has implied that rapamycin may alter the activity of MAPKs including Erk1/2, JNK and/or p38 under various conditions, thus affecting cell proliferation, survival and apoptosis (Benoit et al, 2011; Hahn et al, 2005; Huang et al, 2003; Kato et al, 2013; Kawasaki et al, 2010; Shi et al, 2005). However, it is unknown whether and how rapamycin protects against Cd-induced neuronal apoptosis by preventing ROS from activation of Erk1/2, JNK and/or p38 pathways.…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A

Wang

Yang

et al. 2016

Neuropharmacology

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Cadmium (Cd) is a highly toxic metal that affects the central nervous system. Recently we have demonstrated that inhibition of mTOR by rapamycin rescues neuronal cells from Cd-poisoning. Here we show that rapamycin inhibited Cd-induced mitochondrial ROS-dependent neuronal apoptosis. Intriguingly, rapamycin remarkably blocked phosphorylation of JNK, Erk1/2 and p38 in neuronal cells induced by Cd, which was strengthened by co-treatment with Mito-TEMPO. Inhibition of JNK and Erk1/2 by SP600125 and U0126, respectively, potentiated rapamycin’s prevention from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or MKK1 also potently improved the inhibitory effect of rapamycin on Cd neurotoxicity. Furthermore, pretreatment with SP600125 or U0126, or expression of dominant negative c-Jun or MKK1 enhanced the inhibitory effects of rapamycin or Mito-TEMPO on Cd-induced ROS. Further investigation found that co-treatment with Mito-TEMPO/rapamycin more effectively rescued cells by preventing Cd inactivation of PP2A than treatment with rapamycin or Mito-TEMPO alone. Over-expression of wild-type PP2A reinforced rapamycin or Mito-TEMPO suppression of activated JNK and Erk1/2 pathways, as well as ROS production and apoptosis in neuronal cells in response to Cd. The findings indicate that rapamycin ameliorates Cd-evoked neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A, thereby suppressing activation of JNK and Erk1/2 pathways. Our results underline that rapamycin may have a potential in preventing Cd-induced oxidative stress and neurodegenerative diseases.

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Targeting the JNK Signaling Pathway Potentiates the Antiproliferative Efficacy of Rapamycin in LS174T Colon Cancer Cells

Abstract: Taken together, these results show that rapamycin-induced JNK phosphorylation and activation reduces the antitumor efficacy of rapamycin in LS174T cells.

Cited by 10 publications

References 34 publications

JNK and Macroautophagy Activation by Bortezomib Has a Pro-Survival Effect in Primary Effusion Lymphoma Cells

JNK and Macroautophagy Activation by Bortezomib Has a Pro-Survival Effect in Primary Effusion Lymphoma Cells

Targeting the Mammalian Target of Rapamycin (mTOR) in Cancer Therapy: Lessons from Past and Future Perspectives

Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A

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