ArticleClinical cancer research : an official journal of the American Association for Cancer Research2012
STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 67 citations in OpenAlex.
- Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study.Gynecologic oncology · 2012Trial
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- Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan.Nature genetics · 2025Article
- Unravelling the Mystery inside Cells by Using Single-Molecule Fluorescence Imaging.Journal of imaging · 2023Review
- SENP1 promotes MCL pathogenesis through regulating JAK-STAT5 pathway and SOCS2 expression.Cell death discovery · 2021Article
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- Chemokine-Cytokine Networks in the Head and Neck Tumor Microenvironment.International journal of molecular sciences · 2021Review
- Genome-wide identification of methylated CpG sites in nongenital cutaneous warts.BMC medical genomics · 2020Article
- The Effects of YAP and Its Related Mechanisms in Central Nervous System Diseases.Frontiers in neuroscience · 2020Review
- MicroRNA in Lung Cancer Metastasis.Cancers · 2019Review
- Suppressor of cytokine signalling-2 limits IGF1R-mediated regulation of epithelial-mesenchymal transition in lung adenocarcinoma.Cell death & disease · 2018Article
- SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway.Oncotarget · 2017Article
- miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2017Article
- Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors.Cancer letters · 2017Article
- Turn down genes for WAT? Activation of anti-apoptosis pathways protects white adipose tissue in metabolically depressed thirteen-lined ground squirrels.Molecular and cellular biochemistry · 2016Article
- Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.The Journal of experimental medicine · 2016Article
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8 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe inhibition of c-Src results in a striking reduction in cancer cell invasion, but the effect on cell survival is modest. Defining mechanisms that limit apoptosis following c-Src inhibition could result in an ideal therapeutic approach that both inhibits invasion and leads to apoptosis. In this regard, we discovered a novel feedback loop that results in STAT3 reactivation following sustained c-Src inhibition. Here we define the mechanism underlying this feedback loop and examine the effect of inhibiting it in vivo. EXPERIMENTAL
designWe measured levels and activity of pathway components using PCR, Western blotting, and kinase assays following their manipulation using both molecular and pharmacologic approaches. We used a heterotransplant animal model in which human oral squamous cancer is maintained exclusively in vivo.
resultsFollowing c-Src inhibition, STAT5 is durably inhibited. The inhibition of STAT5A, but not STAT5B, subsequently reduces the expression of suppressors of cytokine signaling 2 (SOCS2). SOCS2 inhibits Janus kinase 2 (Jak2) activity and Jak2-STAT3 binding. SOCS2 expression is necessary for STAT3 inhibition by c-Src inhibitors. Overexpression of SOCS2 is adequate to prevent STAT3 reactivation and to enhance the cytotoxic effects of c-Src inhibition. Likewise, the combination of Jak and c-Src inhibitors led to significantly more apoptosis than either agent alone in vivo.
conclusionsTo our knowledge, ours is the first study that fully defines the mechanism underlying this feedback loop, in which sustained c-Src inhibition leads to diminished SOCS2 expression via sustained inhibition of STAT5A, allowing activation of Jak2 and STAT3, Jak2-STAT3 binding, and survival signals.
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