Bcl-xL and Myeloid cell leukaemia-1 contribute to apoptosis resistance of colorectal cancer cells

Abstract

and immunohistochemistry. Bcl-x L and Mcl-1 protein expression was knocked down or increased in CRC cell lines by applying specific siRNAs or expression plasmids, respectively. After modulation of protein expression, CRC cells were treated with chemotherapeutic agents, an antagonistic epidermal growth factor receptor (EGFR1) antibody, an EGFR1 tyrosine kinase inhibitor, or with the death receptor ligand TRAIL. Apoptosis induction and cell viability were analyzed. RESULTS: Here we show that in human CRC tissue and various CRC cell lines both Bcl-x L and Mcl-1 are expressed. Bcl-x L expression was higher in CRC tissue than in surrounding non-malignant tissue, both on protein and mRNA level. Mcl-1 mRNA expression was significantly lower in malignant tissues. However, protein expression was slightly higher. Viability rates of CRC cells were significantly decreased after knock down of Bcl-x L expression, and, to a lower extent, after knock down of Mcl-1 expression. Furthermore, cells with reduced Bcl-x L or Mcl-1 expression was more sensitive towards oxaliplatin-and irinotecan-induced apoptosis, and in the case of Bcl-x L also towards 5-FU-induced apoptosis. On the other hand, upregulation of Bcl-x L by transfection of an expression plasmid decreased chemotherapeutic drug-induced apoptosis. EGF treatment clearly induced Bcl-x L and Mcl-1 expression in CRC cells. Apoptosis induction upon EGFR1 blockage by cetuximab or PD168393 was increased by inhibiting Mcl-1 and Bcl-x L expression. More strikingly, CD95-and TRAIL-induced apoptosis was increased by Bcl-x L knock down. CONCLUSION: Our data suggest that Bcl-x L and, to a lower extent, Mcl-1, are important anti-apoptotic factors in CRC. Specific downregulation of Bcl-x L is a promising approach to sensitize CRC cells towards chemotherapy and targeted therapy.

Inhibition of NANOG/NANOGP8 Downregulates MCL-1 in Colorectal Cancer Cells and Enhances the Therapeutic Efficacy of BH3 Mimetics

“…However, chemotherapy may not kill colorectal carcinoma that expresses high levels of prosurvival BCL2 proteins (2–4). This supports the development of new treatments to overcome the overexpression of these BCL-2 proteins (5, 6). …”

“…32). In colorectal carcinoma cell lines, ABT-737 has shown poor efficacy as a single agent but the growth inhibition increases when ABT-737 is used in combination with other therapies (3, 5, 6, 12). In this study, the colorectal carcinoma cell lines exhibited low to moderate sensitivity when treated with ABT-737 or ABT-199 as single agents with CX-1 being the most sensitive cell line (Supplementary Table S1).…”

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

“…These observations clearly indicate that HT29 and V9P cancer cells behave as type II cells in which DRinduced apoptosis is controlled mainly by anti-apoptotic Bcl-2 family proteins. 6,25 Interestingly, although Mcl-1, Bcl-2, or Bcl-xL expression levels were unaffected by oxaliplatin, a partial Bcl-xL phosphorylation was induced in both cell lines. Our data show Bcl-xL phosphorylation in response to a DNA-damaging agent.…”

Prognostic role of myeloid cell leukemia‐1 protein (Mcl‐1) expression in human gastric cancer

“…Mcl-1 contains the Bcl-2 homology domains BH 1-3 and a PEST domain and has been considered as a rapidly inducible protein with a short half life [7]. Mcl-1 has been shown to be involved in apoptosis and cell cycle and overexpress in a variety of human cancers such as hepatocelluar carcinoma, colorectal cancer and chronic lymphycytic leukemia [8][9][10]. Although many experiment studies clearly indicate that Mcl-1 plays an important role in the development and progression of malignant tumors, the clinicopathological features of Mcl-1 expression in gastric cancer remains still unclear.…”