Abstract LB-282: Loss of PTP-PEST Promotes Tumor Invasion, Apoptosis Resistance and Activation of STAT3 in Metastatic Colon Cancer.
Cancer research(2013)
摘要
Abstract The transcription factor STAT3 is hyperactivated by phosphorylation on Y705 in over 75% of metastatic colon cancers and is associated with EMT, cancer stem cells, survival and chemoresistance. However, the mechanisms of STAT3 inactivation are not well-defined. Here, we identified the protein tyrosine phosphatase, PTP-PEST, as a novel negative regulator of STAT3 in colon carcinoma cells. Using lentiviral-mediated shRNA silencing of PTP-PEST in HCT116 colon carcinoma cells, we show that PTP-PEST knockdown enhances activation of STAT3. Whereas STAT3 is activated by cell attachment to collagen in control cells expressing non-targeting shRNA, PTP-PEST knockdown leads to constitutive, anchorage-independent STAT3 activity. Silencing of PTP-PEST enhances anchorage-independent survival in soft agar, tumor sphere growth and matrigel invasion in vitro. Consistent with increased invasion and survival, PTP-PEST knockdown cells showed enhanced expression of STAT3 target genes, MMP2 and mcl-1. Significantly, PTP-PEST knockdown enhanced apoptosis resistance in three-dimensional matrigel cultures in response to the chemotherapy drug, 5-fluorouracil (5-FU). PTP-PEST knockdown cells treated with 5-FU in 3-D matrigel spheroid cultures showed increased cell viability, reduced caspase-3 activation and enhanced activation of STAT3 relative to non-targeting controls. Furthermore, in subcutaneous nude mouse xenografts, although overall tumor growth was not affected by PTP-PEST knockdown, immunohistochemistry showed reduced caspase-3 and elevated P-STAT3 levels in these tumors. Intrasplenic injection of PTP-PEST knockdown cells in athymic nude mice resulted in enhanced metastatic potential as assessed by quantitative PCR for human DNA content in mouse liver. Finally, reduced PTP-PEST expression correlates with metastasis in clinical specimens from colon cancer patients. Taken together, these findings suggest that down-regulation of PTP-PEST in colon cancer may promote metastasis through increased invasion and apoptosis resistance, mediated, in part, by enhanced activation of STAT3. Citation Format: Rosario Espejo, Yowjiun Jeng, Camille Johnson, Russ Carmical, Allan Brasier, Celia Chao, Sarita K. Sastry. Loss of PTP-PEST promotes tumor invasion, apoptosis resistance and activation of STAT3 in metastatic colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2013-LB-282
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