Mechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib

Ross, Fiona A.; Hawley, Simon A.; Auciello, Francesca R.; Gowans, Graeme J.; Atrih, Abdelmadjid; Lamont, Douglas J.; Hardie, D. Grahame

doi:10.1016/j.chembiol.2017.05.021

Cited by 58 publications

(53 citation statements)

References 55 publications

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“…Studies on hepatic lipogenesis have targeted nutrient-dependent activation of the AMPK-mTOR-SREBP1 pathway in hepatic de novo lipogenesis (32), and it is well documented that AMPK activation inhibits SREBP1 through mTOR (45). A previous study has reported that sorafenib could activate AMPK indirectly by inhibiting mitochondrial metabolism and increasing cellular AMP: ADP and ADP:ATP ratios (46). Consistent with those findings, we found that the AMPK-mTOR-SREBP1 pathway was activated by reduced ATP levels due to mitochondria damage by sorafenib, thus resulting in the decrease of SCD1 expression ( Figs.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acidsviathe ATP‐AMPK‐mTOR‐SREBP1 signaling pathway

et al. 2019

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Sorafenib is a multikinase inhibitor that is effective in treating advanced liver cancer. Although its mechanism of action through several established cancer‐related protein kinase targets is well‐characterized, sorafenib induces variable responses among human tumors, and the cause for this variation is yet unknown. To investigate the underlying mechanisms, we applied mass spectrometry‐based proteomic analysis to Huh7.5 human liver cancer cells and found that sorafenib significantly affected the expression of the key lipogenic enzymes, especially stearoyl coenzyme A desaturase 1 (SCD1), in these cells. Given that SCD1 catalyzes the most crucial and rate‐limiting step in the synthesis of monounsaturated fatty acids (FAs), we performed a lipidomic analysis, which showed a dramatically altered lipid profile in sorafenib‐treated cells. Detection and analysis of free FAs showed that the levels of monounsaturated FAs, including oleate, were significantly decreased in those cells treated by sorafenib. Addition of oleate protected liver cancer cells from sorafenib‐induced death and alleviated the abnormalities of mitochondrial morphology and function caused by the drug. Treatment with sorafenib suppressed ATP production, resulting in AMPK activation via phosphorylation. Further secondary effects included reduction of the levels of sterol regulatory element‐binding protein 1 (SREBP1) and the phosphorylation of mammalian target of rapamycin (mTOR) in liver cancer cells. These effects were partly abolished in the presence of compound C (an AMPK inhibitor) and ATP and adenosine, and SREBP1c overexpression also could be resistant to the effects of sorafenib, suggesting that the sorafenib‐induced reduction in cell viability was mediated by the ATP‐AMPK‐mTOR‐SREBP1 signaling pathway. Taken together, our results suggest that sorafenib's anticancer activity in liver cancer cells is based on the inhibition of ATP production, SCD1 expression, and monounsaturated FA synthesis. In addition, the decreased monounsaturated FA synthesis further triggered the more serious reduction of ATP production in sorafenib‐treated cells. To our knowledge, this is the first evidence that sorafenib disrupts lipogenesis and triggers liver cancer cell death by targeting SCD1 through the ATP‐AMPK‐mTOR‐SREBP1 pathway.—Liu, G., Kuang, S., Cao, R., Wang, J., Peng, Q., Sun, C. Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acids via the ATP‐AMPK‐mTOR‐ SREBP1 signaling pathway. FASEB J. 33,10089‐10103 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acidsviathe ATP‐AMPK‐mTOR‐SREBP1 signaling pathway

et al. 2019

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“…The intracellular energy status sensor AMPK has been thought to promote cell survival under energy stress . AMPK phosphorylation can be triggered by the excessive ATP consumption and suppressed ATP generation, so as to mediating intracellular energy stress response. In the condition of sorafenib treatment, AMPK has been revealed to be activated since the agent repressed mitochondrial respiration and consequently decreased ATP levels in cardiomyocytes, HCC cells, and breast cancer cells .…”

Section: Discussionmentioning

confidence: 99%

“…[46][47][48] Specifically, activation of AMPK plays a protective role against sorafenibinduced de-energization in hepatocholangiocarcinoma cells, revealing that AMPK depletion potentiated sorafenib treatment efficacy 31 and AMPK activation contributed to sorafenib resistance. It has been widely known that AMPK phosphorylation is mediated by LKB1 45 and Ca 2+ -activated kinase, CaMKK2. 49,50 Nevertheless, endogenous mechanism modulating AMPK activation in sorafenib resistance is poorly understood.…”

Section: F I G U R E 4 Knockdown Of Sesn2 Inhibited Activation Of Aktmentioning

confidence: 99%

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

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“…In cholangiocytes, sorafenib‐induced cAMP/protein kinase A (PKA) ‐ dependent Raf/MEK/ERK signalling activation has been described . Hereby, sorafenib seems to activate AMPK indirectly by inhibiting mitochondrial metabolism and increasing cellular AMP : ADP and/or ADP : ATP ratios .…”

Section: Discussionmentioning

confidence: 99%

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner

Lohmeyer

Nerreter

Dotterweich

et al. 2018

Clinical and Experimental Immunology

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Natural killer (NK) cells play a major role in host immunity against leukaemia and lymphoma. However, clinical trials applying NK cells have not been as efficient as hoped for. Patients treated with rapidly accelerated fibrosarcoma (RAF) inhibitors exhibit increased tumour infiltration by immune cells, suggesting that a combination of RAF inhibitors with immunotherapy might be beneficial. As mitogen-activated protein kinases (MAPKs) such as raf-1 proto-oncogene, serine/threonine kinase (CRAF) regulate NK cell functions, we performed an in-vitro investigation on the potential of clinically relevant short-acting tyrosine kinase inhibitors (TKIs) as potential adjuvants for NK cell therapy: NK cells from healthy human blood donors were thus treated with sorafenib, sunitinib or the pan-RAF inhibitor ZM336372 during ex-vivo expansion. Functional outcomes assessed after washout of the drugs included cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction with/without target cell contact. Paradoxically, sorafenib enhanced NK cell effector functions in a time- and dose-dependent manner by raising the steady-state activation level. Of note, this did not lead to NK cell exhaustion, but enhanced activity against target cells such as K562 or Daudis mediated via the RAS/RAF/extracellular-regulated kinase (ERK) pathway, but not via protein kinase B (AKT). Our data will pave the path to develop a rationale for the considered use of RAF inhibitors such as sorafenib for pre-activation in NK cell-based adoptive immune therapy.

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Mechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib

Cited by 58 publications

References 55 publications

Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acidsviathe ATP‐AMPK‐mTOR‐SREBP1 signaling pathway

Sorafenib kills liver cancer cells by disrupting SCD1‐mediated synthesis of monounsaturated fatty acidsviathe ATP‐AMPK‐mTOR‐SREBP1 signaling pathway

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose- and time-dependent manner

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