Increased expression of cFLIPL in colonic adenocarcinoma

Abstract

During tumour progression, cancer cells use diverse mechanisms to escape from apoptosis-inducing stimuli, which may include receptor internalization, inhibition of signal pathways, and regulation of specific sets of genes. Substantial numbers of colon cancer cells have been observed to express Fas/Fas ligand, but are resistant to Fas-mediated apoptosis, suggesting that colonic tumours might develop specific mechanisms to overcome Fas-mediated apoptosis. Recently, cellular FLICE-like inhibitory protein (cFLIP) has been identified as an endogenous inhibitor of Fas- or other receptor-mediated apoptosis and its altered high expression has a suspected association with tumour development or progression. In an effort to investigate the prevalence of cFLIP(L) alterations in colon carcinomas and their possible implications for the progression of colon cancers, cFLIP(L) expression was analysed in adenocarcinomas and adenomatous polyps of colon, with matched normal tissues, at RNA and protein levels, by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. cFLIP(L) transcripts were constitutively expressed in colon cancers and expression levels were significantly higher in carcinomas than in normal tissues (p<0.05). Overexpression of cFLIP(L) protein was found exclusively in carcinoma cells in all matched sets analysed and approximately three-fold induction was detected in cancer cells (p<0.05). The expression of cFLIP(L) protein was not significantly altered in adenomatous polyps compared with normal tissues. Taken together, these results strongly suggest that abnormal overexpression of cFLIP(L) is a frequent event in colon carcinomas and might contribute to in vivo tumour transformation.

New insights into apoptosis signaling by Apo2L/TRAIL

“…These data indicate that thymocytes and T cells respond in type I mode, whereas hepatocytes and pancreatic b cells behave in type II manner vis-a-vis Fas signaling. Further evidence supports the existence of similar type I versus II mechanisms in Apo2L/TRAIL signaling as well (Figure 2 (Ryu et al, 2001), pancreatic carcinoma (Elnemr et al, 2001), malignant melanoma (Irmler et al, 1997) and Burkitt's lymphoma (Tepper and Seldin, 1999). Another potential determinant is XIAP.…”

c-FLIP inhibits chemotherapy-induced colorectal cancer cell death

“…It is possible that the relatively high levels of c-FLIP S in the two c-FLIP S -overexpressing cell lines (in particular HFS44) may be superphysiological and promote DISC-independent clustering and activation of caspase 8. In contrast, the levels of c-FLIP L overexpression in the HFL17 and HFL24 cell lines (B4-fold) are similar to the levels of overexpression observed by Ryu et al (2001) in colonic tumours. The different effects of overexpressing each splice form may be due to c-FLIP L being a more potent inhibitor of death receptor-mediated apoptosis (Irmler et al, 1997).…”

“…Our findings indicate that overexpression of c-FLIP L inhibits apoptosis of CRC cells in response to the chemotherapeutic agents used in the treatment of CRC. This has particular clinical relevance given the high incidence of c-FLIP L overexpression observed in colon cancer (Ryu et al, 2001). Interestingly, c-FLIP S overexpression failed to protect CRC cells from 5-FU-and OXA-induced apoptosis, and only moderately protected against CPT-11-induced apoptosis.…”

“…Furthermore, clinical studies have demonstrated significantly elevated c-FLIP expression in colorectal and gastric tumours (Ryu et al, 2001;Zhou et al, 2004), suggesting that c-FLIP may be a relevant clinical target not only in CRC but also in gastric cancer, where 5-FU-based chemotherapy regimens are also used. Moreover, our data suggest that c-FT therapeutic strategies may be effective against colorectal tumours irrespective of p53 mutational status.…”

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

“…FLIP has been found to be overexpressed in many human cancers (Ryu et al, 2001;Zhou et al, 2004;Valnet-Rabier et al, 2005), and has emerged through our work and that of others, as a potential anti-cancer drug target (Hyer et al, 2005;Wilson et al, 2007). Furthermore, XIAP has been found to be overexpressed in several cancers, and small molecule and antisense approaches to target XIAP are in development (Hu et al, 2003;LaCasse et al, 2006).…”