alpha-Tocopheryl succinate induces DR4 and DR5 expression by a p53-dependent route: Implication for sensitisation of resistant cancer cells to TRAIL apoptosis

FEBS Letters. 2006 Feb 28; [Epub ahead of print] [Link]

Marco Tomasetti^a, Ladislav Andera^b, Renata Alleva^c, Battista Borghi^c, Jiri Neuzil^{b, d} and Antonio Procopio^{a, e}

^aDepartment of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, via Ranieri 1, Ancona, Italy
^bLaboratory of Cell Signaling and Apoptosis, Institute of Molecular Genetics, Czech Academy of Sciences, Czech Republic
^cDepartment of Anaesthesiology, IRCCS Orthopaedic Institute “Rizzoli”, Bologna, Italy
^dApoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld., Australia
^eCenter of Cytology, Italian National Research Center on Aging (INRCA-IRCCS), Ancona, Italy

Received 16 December 2005;  revised 17 February 2006;  accepted 21 February 2006.  Available online 28 February 2006.

Abstract

We evaluated the ability of α-tocopheryl succinate (α-TOS) to sensitise TRAIL-resistant malignant mesothelioma (MM) cells to TRAIL-induced apoptosis. We show that α-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 α-TOS restored expression of DR4 and DR5. The ability of α-TOS to modulate expression of pro-apoptotic genes may play a role in sensitisation of tumour cells to immunological stimuli.

Keywords: Malignant mesothelioma; TRAIL; α-TOS; p53; DR5; DR4

Abbreviations: 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