Alpha-tocopheryl succinate induces DR4 and DR5 expression by a p53-dependent route: implication for sensitisation of resistant cancer cells to TRAIL apoptosis |
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Authors: | Tomasetti Marco Andera Ladislav Alleva Renata Borghi Battista Neuzil Jiri Procopio Antonio |
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Affiliation: | Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, via Ranieri 1, Ancona, Italy. mtomasetti@virgilio.it |
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Abstract: | We evaluated the ability of alpha-tocopheryl succinate (alpha-TOS) to sensitise TRAIL-resistant malignant mesothelioma (MM) cells to TRAIL-induced apoptosis. We show that alpha-TOS activates expression of DR4/DR5 in a p53-dependent manner and re-establishes sensitivity of resistant MM cells to TRAIL-mediated apoptosis, as documented in p53wt MM cells but not in their p53null counterparts. MM cells selected for TRAIL resistance expressed low cell surface levels of DR4 and DR5. Treatment with sub-lethal doses of alpha-TOS restored expression of DR4 and DR5. The ability of alpha-TOS to modulate expression of pro-apoptotic genes may play a role in sensitisation of tumour cells to immunological stimuli. |
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Keywords: | DR, death receptor FLIP, FLICE inhibitory protein MM, malignant mesothelioma ActD, actinomycin D Q-PCR, quantitative real-time PCR siRNA, small interfering RNA α-TOS, α-tocopheryl succinate TR, TRAIL-resistant TRAIL, TNF-related apoptosis-inducing ligand |
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