Disruption of the Mouse Protein Tyrosine Kinase 6 Gene Prevents STAT3 Activation and Confers Resistance to Azoxymethane

Abstract

Background & Aims Protein tyrosine kinase 6 (PTK6) is expressed throughout the gastrointestinal tract and is a negative regulator of proliferation that promotes differentiation and DNA-damage induced apoptosis in the small intestine. PTK6 is not expressed in normal mammary gland, but is induced in most human breast tumors. Signal transducer and activator of transcription 3 (STAT3) mediates pathogenesis of colon cancer and is a substrate of PTK6. We investigated the role of PTK6 in colon tumorigenesis. Methods Ptk6 +/+ and Ptk6 −/− mice were injected with azoxymethane alone or in combination with dextran sodium sulfate; formation of aberrant crypt foci (ACF) and colon tumors was examined. Effects of disruption of Ptk6 on proliferation, apoptosis, and STAT3 activation were examined by immunoblot and immunohistochemical analyses. Regulation of STAT3 activation was examined in the HCT116 colon cancer cell line and young adult mouse colon (YAMC) cells. Results Ptk6 −/− mice developed fewer azoxymethane-induced ACF and tumors. Induction of PTK6 increased apoptosis, proliferation, and STAT3 activation in Ptk6 +/+ mice injected with azoxymethane. Disruption of Ptk6 impaired STAT3 activation following azoxymethane injection, and reduced active STAT3 levels in Ptk6 −/− tumors. Stable knockdown of PTK6 reduced basal levels of active STAT3, as well as activation of STAT3 by epidermal growth factor in HCT116 cells. Disruption of Ptk6 reduced activity of STAT3 in YAMC cells. Conclusions PTK6 promotes STAT3 activation in the colon following injection of the carcinogen azoxymethane and regulates STAT3 activity in mouse colon tumors and in the HCT116 and YAMC cell lines. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice.

PTK6 Potentiates Gemcitabine-Induced Apoptosis by Prolonging S-phase and Enhancing DNA Damage in Pancreatic Cancer

“…Previous studies of the role of PTK6 in mediating DNA damage in nonmalignant cells (15,27,28) and in other malignancies (29) have yielded conflicting results that likely reflect differences in the genetic background of host cells. Gierut and colleagues emphasized in their report that PTK6 signaling outcomes in cellular models are context-dependent and demonstrated the effect of PTK6 knockdown on radiation-induced apoptosis was different depending on the p53 gene mutation in their colon cancer cell line model (28,29).…”

“…Gierut and colleagues emphasized in their report that PTK6 signaling outcomes in cellular models are context-dependent and demonstrated the effect of PTK6 knockdown on radiation-induced apoptosis was different depending on the p53 gene mutation in their colon cancer cell line model (28,29). In addition, the localization of PTK6 may be important in the role of overexpressed PTK6 in pancreatic cancer.…”

PTK6 (protein tyrosine kinase 6)

“…In human colon cancer cell lines and in murine colon tissue, PTK6 negatively regulates β-catenin transcriptional activity (PalkaHamblin et al, 2010). PTK6 has a tumor-promoting role in the colon as disruption of the Ptk6 gene impaired carcinogen-induced tumorigenesis in mice (Gierut et al, 2011) and PTK6 promotes survival of colon cancer cell lines following DNA damaging treatments including γ-irradiation and chemotherapeutic drugs via STAT3 activation (Gierut et al, 2012). Targeting PTK6 to plasma membrane enhanced proliferation, survival, migration and anchorageindependent growth in HEK293 cells, while nuclear targeting inhibited the invasive phenotype (Kim and Lee, 2009).…”

“…Disruption of Ptk6 impairs carcinogen induced tumorigenesis in mice, suggesting a tumorpromoting role for the kinase in the colon as well (Gierut et al, 2011). In human colon cancer cell lines, PTK6 promotes cell survival following DNA damaging treatments including γ-irradiation and chemotherapeutic drugs via STAT3 activation (Gierut et al, 2012).…”

Evolution of breast cancer therapeutics: Breast tumour kinase’s role in breast cancer and hope for breast tumour kinase targeted therapy

“…STAT3 and STAT5 are also recognised as substrates of Brk and are involved in cellular processes leading to cell proliferation, migration and survival [79][80][81] . STAT3 is regarded as an oncogene, with tyrosine phosphorylation of STAT3 connected to breast cancer development as discussed in [79] .…”