Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

Liu, Jing; Chang, Fen; Li, Fang; Fu, Hui; Wang, Jinlan; Zhang, Shangli; Zhao, Jing; Yin, Deling

doi:10.1016/j.bbrc.2015.05.042

Cited by 138 publications

(95 citation statements)

References 29 publications

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“…Some reports have shown that autophagy could be regulated by ERK and p38 MAPK pathways under different conditions282930. In this study, suppressing the activity of ERK signaling pathway with its specific inhibitor U0126 led to reduced autophagic level, as reflected by the blocking of LC3 conversion in CSE-treated Beas-2B cells.…”

Section: Resultsmentioning

confidence: 49%

“…ERK1/2 can be also suppressed by amino acids to inhibit autophagy29. Moreover, p38 MAPK inhibitor was shown to directly abrogate palmitate-induced conversion of LC3I to LC3II28. Our data revealed that suppression of ERK phosphorylation reduced autophagy in CSE-treated Beas-2B cells, implying a positively regulating role of ERK MAPK in CSE-induced autophagy.…”

Section: Discussionmentioning

confidence: 60%

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Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

Wang

et al. 2016

Sci Rep

101

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Cigarette smoke (CS) is a major risk of chronic obstructive pulmonary disease (COPD), contributing to airway inflammation. Our previous study revealed that silymarin had an anti-inflammatory effect in CS-exposed mice. In this study, we attempt to further elucidate the molecular mechanisms of silymarin in CS extract (CSE)-induced inflammation using human bronchial epithelial cells. Silymarin significantly suppressed autophagy activation and the activity of ERK/p38 mitogen-activated protein kinase (MAPK) pathway in Beas-2B cells. We also observed that inhibiting the activity of ERK with specific inhibitor U0126 led to reduced autophagic level, while knockdown of autophagic gene Beclin-1 and Atg5 decreased the levels of ERK and p38 phosphorylation. Moreover, silymarin attenuated CSE-induced upregulation of inflammatory cytokines TNF-α, IL-6 and IL-8 which could also be dampened by ERK/p38 MAPK inhibitors and siRNAs for Beclin-1 and Atg5. Finally, we validated decreased levels of both autophagy and inflammatory cytokines (TNF-α and KC) in CS-exposed mice after silymarin treatment. The present research has demonstrated that CSE-induced autophagy in bronchial epithelia, in synergism with ERK MAPK pathway, may initiate and exaggerate airway inflammation. Silymarin could attenuate inflammatory responses through intervening in the crosstalk between autophagy and ERK MAPK pathway, and might be an ideal agent treating inflammatory pulmonary diseases.

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Section: Resultsmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 60%

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

Wang

et al. 2016

Sci Rep

101

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“…MAPKs, including ERK1/2, JNK and p38, are a family of serine/threonine kinases that regulate a variety of cellular events, including proliferation and apoptosis (16,22,23). A previous study demonstrated that various stress stimuli, including the oxidative stress caused by ROS, may induce potential activation of MAPK signaling pathways (24). In addition, the activation of JNK contributes to stress-induced apoptosis (25).…”

Section: Discussionmentioning

confidence: 99%

Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways

et al. 2016

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Abstract. Phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK) signaling cascades have significant roles in cell proliferation, survival, angiogenesis and metastasis of tumor cells. Eupatilin, one of the major compounds present in Artemisia species, has been demonstrated to have antitumor properties. However, the effect of eupatilin in renal cell carcinoma (RCC) remains to be elucidated. Therefore, the present study investigated the biological effects and mechanisms of eupatilin in RCC cell apoptosis. The results of the present study demonstrated that eupatilin significantly induced cell apoptosis and enhanced the production of reactive oxygen species (ROS) in 786-O cells. In addition, eupatilin induced phosphorylation of p38α (Thr180/Tyr182), extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase 1/2 (Thr183/Tyr185), and decreased the phosphorylation of PI3K and AKT in 786-O cells in a concentration-dependent manner. Furthermore, the ROS inhibitor N-acetyl-L-cysteine was able to rescue the MAPK activation and PI3K/AKT inhibition induced by eupatilin. Taken together, the results of the present study provide evidence that inhibition of eupatilin induces apoptosis in human RCC via ROS-mediated activation of the MAPK signaling pathway and inhibition of the PI3K/AKT signaling pathway. Thus, eupatilin may serve as a potential therapeutic agent for the treatment of human RCC.

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“…The FASNi orlistat has been shown to block palmitate synthesis [42]. Interestingly, many studies have shown that palmitate levels are linked to ER stress and autophagy regulation [43–45]. Therefore, we investigated if bortezomib effects could be potentiated by orlistat co-treatment in analogy to the observation with autophagy inhibitors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This approach of re-positioning conventional drugs to target autophagy and induce cancer cell death was already shown for several therapeutics [63]. Orlistat might impair the autophagic machinery due to a reduction in palmitate levels [43–45]. Our group has previously shown that orlistat-induced cell death in MCL is indeed palmitate-dependent [24].…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

et al. 2018

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BackgroundMantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL.MethodsThe effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition.ResultsIn this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples.ConclusionOur data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0657-6) contains supplementary material, which is available to authorized users.

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Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

Cited by 138 publications

References 29 publications

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways

Cyclin D1-CDK4 activity drives sensitivity to bortezomib in mantle cell lymphoma by blocking autophagy-mediated proteolysis of NOXA

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