Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential

Abstract

Recent data suggest that signal transduction may have a critical role in the development and regulation of the metastatic phenotype. Here, we investigated the role of c-Src activation in the process of human colon cancer metastasis to the liver. Our data, derived from two di erent sets of human colon cancer cell line metastatic variants, suggest that not only do highly-metastatic cells display constitutively elevated c-Src protein kinase activity when compared to poorly metastatic cells, but also that receptor tyrosine kinases participate in the ligand-activation of c-Src above basal levels. Speci®cally, the epidermal growth factor receptor (EGFR), p185HER2/Neu and the hepatocyte growth factor receptor (c-Met) appear to be linked to the process because they preferentially activate c-Src in highlymetastatic cells. EGFR was found to associate with c-Src in colon cancer cells and speci®c inhibitors of the EGFR resulted in a reduction of c-Src activity to basal levels. In addition, c-Src transfectants displayed partially-activated EGFRs, suggesting a feedback role for c-Src in the regulation of the EGFR. p185HER2/Neu was also identi®ed in immunocomplexes of c-Src following ligand activation of the EGFR, but only in highly-metastatic cells. Collectively, these observations suggest a paradigm whereby c-Src interacts with multiple cell-surface growth factors in a catalytic fashion for the development of tumor cells with metastatic potential.

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

“…A number of human primary tumours and tumour-derived cell lines including leukaemias possess elevated Src kinase activities (Rosen et al, 1986;Ottenhoff-Kalff et al, 1992;Talamonti et al, 1993;Mao et al, 1997;Donato et al, 2003). For instance, Lyn and Hck have been implicated in the oncogenic activity of Bcr-Abl in haematopoietic cells (Danhauser-Riedl et al, 1996;Hu, Nature genetics, 2004) and with the use of dominant-negative src mutants or pharmacological inhibitors have confirmed that these two kinases contribute to the Bcr-Abl-induced Tel-Abl induces oncogenic signalling via Hck C Pecquet et al Bcr-Abl-transformed haematopoietic cells.…”

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

“…In this context, several candidates have been suggested to disrupt the SH2-pTyr529 intramolecular interaction. These include growth factor receptors, through their association with SFK-SH2 (Mao et al, 1997), and tyrosine phosphatases that dephosphorylate pTyr529 (Liang et al, 2007;Zhu et al, 2007;Zheng et al, 2008). Although probably activated in a subset of tumours, they may not account for the kinase deregulation observed in CRC.…”

c-Src Antisense Complexed with PAMAM Denderimes Decreases of c-Src Expression and EGFR-Dependent Downstream Genes in the Human HT-29 Colon Cancer Cell Line

“…Therefore, inhibitors of Src have a key role in cancer treatment (Summy et al, 2005) and Src family kinases can become important targets for anti-cancer therapy in the future (Summy & Gallick, 2003). In addition, c-Src is over-expressed in a HT29 cell line of colon cancer and plays an important role in the development of metastatic stage of primary human colorectal cancer Termuhlen et al, 1993;Mao et al, 1997). Previous study has shown that c-Src antisense oligonucleotides can silent the c-Src expression in the cancer cells (Charles et al, 1997;Irby & Yeatman, 2000).…”