%0 Journal Article
%T Small interfering RNA targeting mcl-1 enhances proteasome inhibitor-induced apoptosis in various solid malignant tumors
%A Wei Zhou
%A Jingzi Hu
%A Haimei Tang
%A Da Wang
%A Xuefeng Huang
%A Chao He
%A Hongbo Zhu
%J BMC Cancer
%D 2011
%I BioMed Central
%R 10.1186/1471-2407-11-485
%X Different human cancer cell lines were treated with proteasome inhibitors. Western blot were used to investigate the expression of Mcl-1 and activation of mitochondrial apoptotic signaling. Cell viability was investigated using SRB assay, and induction of apoptosis was measured using flow cytometry.We found elevated Mcl-1 level in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human ovarian cancer cell line SKOV3; and human lung cancer cell line H1299, but not in human breast cancer cell line MCF7 after they were treated with bortezomib. This dramatic Mcl-1 accumulation was also observed when cells were treated with other two proteasome inhibitors, MG132 and calpain inhibitor I (ALLN). Moreover, our results showed Mcl-1 accumulation was caused by stabilization of the protein against degradation. Reducing Mcl-1 accumulation by Mcl-1 siRNA reduced Mcl-1 accumulation and enhanced proteasome inhibitor-induced cell death and apoptosis, as evidenced by the increased cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase.Our results showed that it was not only Bik but also Mcl-1 accumulation during the treatment of proteasome inhibitors, and combining proteasome inhibitors with Mcl-1 siRNA would enhance the ultimate anticancer effect suggesting this combination might be a more effective strategy for cancer therapy.Proteasome inhibitors represent a new class of agents for cancer therapeutics [1,2]. The 26S proteasome is a 2, 000-kDa multimeric cylindrical complex comprising a 20S catalytic core and a 19S regulatory subunit [3]. This structure is a promising target for cancer therapy because it regulates the crucial process of proteasome-mediated protein degradation, which involves many proteins such as cyclins, caspases, Bcl-2 and the nuclear factor of ¦ĘB (NF-¦ĘB) [2,4]. Inhibiting proteasome activity leads to the accumulation of these proteins, resulting in cell cycle arrest and apoptosis. Bortezomib, a specific and selective inhibitor of 26S prote
%U http://www.biomedcentral.com/1471-2407/11/485