PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Iansante, Valeria; Choy, Pui Man; Fung, S.; Liu, Ying; Chai, Jian Guo; Dyson, Julian; Río, Alberto Del; D’Santos, Clive S.; Williams, Roger; Chokshi, Shilpa; Anders, Robert A.; Bubici, Concetta; Papa, Salvatore

doi:10.1038/ncomms8882

Cited by 189 publications

(208 citation statements)

References 62 publications

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“…Previous studies also showed that tumor suppressor genes, daf-16/ Foxo, daf-18/Pten, and lin-35/Rb are required for promoting C. elegans starvation survival (Baugh and Sternberg 2006;Cui et al 2013). Starvation or fasting has recently been investigated in cancer therapy (Naveed et al 2014;Cangemi et al 2016), as tumor cells are thought to be more susceptible to starvation due to the Warburg effect (Iansante et al 2015). Results from this study and previous work using C. elegans may suggest that cancer cells, that commonly harbor mutations in tumor suppressor genes, are highly sensitive to starvation stress.…”

Section: Discussionmentioning

confidence: 99%

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

Cui¹,

Wang²,

Cavaleri³

et al. 2017

Genetics

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Our understanding of the cellular mechanisms by which animals regulate their response to starvation is limited, despite the strong relevance of the problem to major human health issues. The L1 diapause of Caenorhabditis elegans, where first-stage larvae arrest in response to a food-less environment, is an excellent system to study this mechanism. We found, through genetic manipulation and lipid analysis, that biosynthesis of ceramide, particularly those with longer fatty acid side chains, critically impacts animal survival during L1 diapause. Genetic interaction analysis suggests that ceramide may act in both insulin-IGF-1 signaling (IIS)-dependent and IISindependent pathways to affect starvation survival. Genetic and expression analyses indicate that ceramide is required for maintaining the proper expression of previously characterized starvation-responsive genes, genes that are regulated by the IIS pathway and tumor suppressor Rb, and genes responsive to pathogen. These findings provide an important insight into the roles of sphingolipid metabolism, not only in starvation response, but also in aging and food-response-related human health problems.

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Section: Discussionmentioning

confidence: 99%

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

Cui¹,

Wang²,

Cavaleri³

et al. 2017

Genetics

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“…PARP14 has also been reported to drive interleukin 4‐triggered gene expression via activation of STAT6 and interacting with the cytokine‐induced signaling transducer . Importantly, the overexpression of PAPR14 has been reported in various solid cancers, such as hepatocellular carcinoma (HCC), glioblastoma, gastric cancer, breast cancer, and lung cancer . Especially in HCC, PARP14 could stimulate the proliferation, survival, chemosensitivity, and the Warburg effect of cancer cells by suppressing c‐Jun NH2‐terminal kinase (JNK)‐1‐dependent pyruvate kinase M1/2 (PKM2) activation and phosphorylation (PAPR14‐JNK1‐PKM2 axis) .…”

Section: Introductionmentioning

confidence: 99%

PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF‐κB pathway

Yao

Chen

Shi

et al. 2019

Molecular Carcinogenesis

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Pancreatic cancer (PC) is the most fatal gastrointestinal malignancy in the world, with a 5‐year relative survival of only 8%. Poly(ADP‐ribose) polymerase (PARP)14, a member of the macro‐PARP subfamily proteins, has been reported to participate in various biologic and pathologic processes in multiple cancers. The roles and underlying molecular mechanisms of PARP14 in PC carcinogenesis, however, remain to be elucidated. In this study, we for the first time discovered that PARP14 was highly expressed in human primary PC specimens and significantly correlated with poor patient prognosis. Using loss‐of‐function studies in vitro and in vivo, we showed that the knockdown of PARP14 led to enhanced apoptosis, repressed proliferation, and gemcitabine (GEM) resistance of PC cells. Further investigations revealed that PARP14 was significantly overexpressed in GEM‐resistant PC cells (SW1990/GZ). And silencing of PARP14 significantly reversed the GEM resistance of SW1990/GZ cells. To the mechanism, PARP14 could stimulate PC progression by the activation of nuclear factor‐κB (NF‐κB) signaling pathway. And inhibition of NF‐κB signal could significantly reverse PARP14–overexpression triggered PC carcinogenesis. In conclusion, PARP14 could promote PC cell proliferation, antiapoptosis, and GEM resistance via NF‐κB signaling pathway, highlighting its potential role as a therapeutic target for PC.

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“…HCC is frequently associated with enhanced glycolysis and increased expression of glycolytic enzymes . This reprogrammed cancer metabolism is known as the Warburg effect .…”

mentioning

confidence: 99%

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

Dai

et al. 2017

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC.

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PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Cited by 189 publications

References 62 publications

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF‐κB pathway

By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma

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