Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3

Gu, Fangming; Li, Quan‐Lin; Gao, Qiang; Jiang, Jiahao; Huang, Xiaoyong; Pan, Jinfeng; Fan, Jian‐Gao; Zhou, Jian

doi:10.3748/wjg.v17.i34.3922

Cited by 81 publications

(69 citation statements)

References 30 publications

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“…ERK1/2 is believed to modulate STAT3 activity through phosphorylation at Ser727 (39,40). The tumor suppression caused by sorafenib has been linked at least in part to the dephosphorylation of STAT3 induced by inhibition of the MEK/ERK-pathway (41). Our results showed a reduction in p-STAT3 (Ser727) induced by RG7356 after þ4.5 and þ8 hours (Fig.…”

Section: Confirmation Of Phosphoproteomics Resultssupporting

confidence: 60%

Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist

Weigand

Herting²,

Maisel³

et al. 2012

Cancer Research

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The cell surface glycoprotein CD44 plays an important role in the development and progression of various tumor types. RG7356 is a humanized antibody targeting the constant region of CD44 that shows antitumor efficacy in mice implanted with CD44-expressing tumors such as MDA-MB-231 breast cancer cells. CD44 receptor seems to function as the main receptor for hyaluronic acid and osteopontin, serving as coreceptor for growth factor pathways like cMet, EGFR, HER-2, and VEGFR and by cytoskeletal modulation via ERM and Rho kinase signaling. To assess the direct impact of RG7356 binding to the CD44 receptor, a global mass spectrometry-based phosphoproteomics approach was applied to freshly isolated MDA-MB-231 tumor xenografts. Results from a global phosphoproteomics screen were further corroborated by Western blot and ELISA analyses of tumor lysates from CD44-expressing tumors. Short-term treatment of tumor-bearing mice with RG7356 resulted in modifications of the MAPK pathway in the responsive model, although no effects on downstream phosphorylation were observed in a nonresponsive xenograft model. Taken together, our approach augments the value of other high throughput techniques to identify biomarkers for clinical development of targeted agents.

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Section: Confirmation Of Phosphoproteomics Resultssupporting

confidence: 60%

Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist

Weigand

Herting²,

Maisel³

et al. 2012

Cancer Research

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“…Sorafenib has been shown to inhibit JAK2 activation (29), which could explain its effect on p97/VCP phosphorylation. However, the effects of sorafenib on JAK2 remain controversial (30), and more work is needed to identify the kinases responsible for p97/VCP tyrosine phosphorylation in the liver.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death

Higa

Taouji

et al. 2012

Molecular Cancer Therapeutics

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The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA þ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients.

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“…In addition, Chen and coworkers recently reported that a novel obatoclax derivative, SC-2001, can induce apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation [265]. Sorafenib has already been reported to inhibit both the growth and metastasis of HCC by blocking STAT3 activation [266].…”

Section: Pharmacological Inhibition Of Stat3 Activation Pathway In Hccmentioning

confidence: 99%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3

Abstract: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.

Cited by 81 publications

References 30 publications

Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist

Global Quantitative Phosphoproteome Analysis of Human Tumor Xenografts Treated with a CD44 Antagonist

Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

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