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Clin Cancer Res. 2012 Jan 1;18(1):127-39. doi: 10.1158/1078-0432.CCR-11-1889. Epub 2011 Nov 16.

STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma.

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1
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

PURPOSE:

The 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 DESIGN:

We 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.

RESULTS:

Following 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.

CONCLUSIONS:

To 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.

PMID:
22090359
PMCID:
PMC3251692
DOI:
10.1158/1078-0432.CCR-11-1889
[Indexed for MEDLINE]
Free PMC Article

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