[Show abstract][Hide abstract] ABSTRACT: Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.
[Show abstract][Hide abstract] ABSTRACT: Alteration of methylation status has been recognized as a possible epigenetic mechanism of selection during tumorigenesis in pancreatic cancer. This type of cancer is characterized by poor prognosis partly due to resistance to conventional drug treatments. We have used microarray technology to investigate the changes in global gene expression observed after treatment of different pancreatic cancer cell lines with the methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). We have observed that this agent is able to inhibit to various degrees the growth of three pancreatic cancer cell lines. In particular, this inhibition was associated with induction of interferon (IFN)-related genes, as observed in other tumour types. Thus, expression of STAT1 seems to play a key role in the cellular response to treatment with the cytosine analogue. Moreover, we found increased p21(WAF1) and gadd45A expression to be associated with the efficacy of the treatment; this induction may correlate with activation of the IFN signalling pathway. Expression of the p16(INK) protein was also linked to the ability of cells to respond to 5-aza-CdR. Finally, genome-wide demethylation induced sensitization that significantly increased response to further treatment with various chemotherapy agents.
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.