Proteasome inhibitor MG132 sensitizes HPV-positive human cervical cancer cells to rhTRAIL-induced apoptosis.

摘要: In cervical carcinogenesis, the p53 tumor suppressor pathway is disrupted by HPV (human papilloma virus) E6 oncogene expression. targets for rapid proteasome-mediated degradation. We therefore investigated whether proteasome inhibition MG132 could restore wild-type levels and sensitize HPV-positive cancer cell lines to apoptotic stimuli such as rhTRAIL (recombinant human TNF-related apoptosis inducing ligand). a panel of lines, CaSki was highly, HeLa intermediate SiHa not sensitive rhTRAIL-induced apoptosis. strongly sensitized in caspase-dependent time-dependent manner. massively induced TRAIL receptor DR4 DR5 membrane expression HeLa, whereas only upregulated from almost undetectable high levels. Antagonistic antibody partially inhibited induction but had no effect on SiHa. Inhibition E6-mediated proteasomal degradation resulted elevated active demonstrated small interfering RNA (siRNA) p21 upregulation. Although siRNA MG132-induced upregulation SiHa, observed. plus enhanced caspase 8 3 activation concomitant cleavage X-linked inhibitor (XIAP), particularly HeLa. addition, 9 observed Downregulation XIAP using combination with be added induce conclusion, independent p53. Our results indicate that also inactivation contribute sensitization lines. Combining inhibitors may therapeutically useful treatment.