PKCε-mediated c-Met endosomal processing directs fluctuant c-Met-JNK-paxillin signaling for tumor progression of HepG2

Hu, Chi-Tan; Cheng, Chuan-Chu; Wu, Jia-Ru; Pan, Siou-Mei; Wu, Wen-Sheng

doi:10.1016/j.cellsig.2015.02.031

Cited by 20 publications

(18 citation statements)

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“…In our previous studies, ROS-dependent activation of MAPK including Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK), well known to mediate tumor progression [ 24 , 25 ], were required for progression of HepG2 induced by TPA and HGF [ 8 , 9 , 19 , 21 , 22 ]. Moreover, JNK activation was required for constitutive migration of HCC329 [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

“…The tumor microenvironment of HCC contains a lot of metastatic factors including transforming growth factor β (TGFβ) [ 2 ] and hepatocyte growth factor (HGF) [ 3 , 4 ], which are capable of triggering HCC metastasis. Paxillin, one of the adaptor molecules critical for integrating the focal adhesion signaling [ 5 – 7 ], is known to be involved in HCC progression triggered by HGF [ 8 , 9 ], integrin engagement [ 10 ] or overexpression of P21-activated protein kinase [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

You

et al. 2015

Oncotarget

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One of the signaling components involved in hepatocellular carcinoma (HCC) progression is the focal adhesion adaptor paxillin. Hydrogen peroxide inducible clone-5 (Hic-5), one of the paralogs of paxillin, exhibits many biological functions distinct from paxillin, but may cooperate with paxillin to trigger tumor progression. Screening of Hic-5 in 145 surgical HCCs demonstrated overexpression of Hic-5 correlated well with intra- and extra-hepatic metastasis. Hic-5 highly expressed in the patient derived HCCs with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. Blockade of Hic-5 expression prevented constitutive migration of HCC329 and HCC353 and HGF-induced cell migration of HCC340. HCC329Hic-5(−), HCC353Hic-5(−), HCC372Hic-5(−), the HCCs stably depleted of Hic-5, exhibited reduced motility compared with each HCC expressing Scramble shRNA. Moreover, intra/extrahepatic metastasis of HCC329Hic-5(−) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promoted its progression. Constitutive and HGF-induced Hic-5 expression in HCCs were suppressed by the reactive oxygen species (ROS) scavengers catalase and dithiotheritol and c-Jun N-terminal kinase (JNK) inhibitor SP600125. On the contrary, depletion of Hic-5 blocked constitutive and HGF-induced ROS generation and JNK phosphorylation in HCCs. Also, ectopic expression of Hic-5 enhanced ROS generation and JNK phosphorylation. These highlighted that Hic-5 plays a central role in the positive feedback ROS-JNK signal cascade. Finally, the Chinese herbal derived anti-HCC peptide LZ-8 suppressed constitutive Hic-5 expression and JNK phosphorylation. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

You

et al. 2015

Oncotarget

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“…Therefore, combination of conventional anti‐cancer treatment with more specific interference with Met targeting to late endosomes, formation of specific signaling complexes on late endosomes or their activation from late endosomes might possibly be an alternative strategy in the future cancer therapies in addition to specific anti Met drugs being tested now on patients in clinical trials. This possibility was originally demonstrated on HGF/Met signaling dependent tumor progression, stimulated by two distinct activating mutations in the kinase domain of Met [Joffre et al, 2011] and shown recently also in a hepatocellular carcinoma (HCC) model [Hu et al, 2015]. HGF‐induced intrahepatic metastasis in mice, injected with the human hepatoma cell line HepG2, were prevented by Dynasore, the inhibitor of dynamin and endocytosis, suggesting novel therapeutic endosomal targets for the treatment of HGF‐induced HCC.…”

Section: Combinatorial Therapy and Future Prospectsmentioning

confidence: 99%

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

Stasyk

Huber

2015

J of Cellular Biochemistry

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The endo/lysosomal system in cells provides membranous platforms to assemble specific signaling complexes and to terminate signal transduction, thus, is essential for physiological signaling. Endocytic organelles can significantly extend signaling of activated cell surface receptors, and may additionally provide distinct locations for the generation of specific signaling outputs. Failures of regulation at different levels of endocytosis, recycling, degradation as well as aberrations in specific endo/lysosomal signaling pathways, such as mTORC1, might lead to different diseases including cancer. Therefore, a better understanding of spatio‐temporal compartmentalization of sub‐cellular signaling might provide an opportunity to interfere with aberrant signal transduction in pathological processes by novel combinatorial therapeutic approaches. J. Cell. Biochem. 117: 836–843, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.

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“…Bim also increases paxillin phosphorylation on Ser178 induced by HGF (Hu, Cheng, Pan, Wu, & Wu, ). HGF (Hu, Cheng, Wu, Pan, & Wu, ) and P21‐activated protein kinase (Pak1) (Ching et al, ) induce p‐JNK, that in turn uses paxillin as its putative substrate (Huang et al, ) to promote HCC progression. Interestingly, activation of both PKC and ERK are required for oxidation of HSP60 and protein disulfide isomerase (PDI) as well as for production of ROS induced by HGF (Lin et al, ).…”

Section: Introductionmentioning

confidence: 99%

Human hepatocellular carcinoma: Protection by melatonin

Mortezaee

2018

Journal Cellular Physiology

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Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a multi-tasking hormone that has long been known for its anti-cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen-activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)- and autophagy-mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor-derived exosomes. Both pro-and anti-oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family.

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PKCε-mediated c-Met endosomal processing directs fluctuant c-Met-JNK-paxillin signaling for tumor progression of HepG2

Cited by 20 publications

References 55 publications

Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

Human hepatocellular carcinoma: Protection by melatonin

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