Tocopherol-associated protein-1 accelerates apoptosis induced by alpha-tocopheryl succinate in mesothelioma cells.
Alpha-tocopheryl succinate (alpha-TOS), a redox-silent analogue of vitamin E, induces apoptosis in multiple cell lines in a selective manner, by activating the intrinsic pathway. Since it is a highly hydrophobic compound, it may require a carrier protein for its trafficking to intracellular targets like mitochondria. We studied the role of the ubiquitous tocopherol-associated protein-1 (TAP1 or sec14-like 2) in apoptosis induction by alpha-TOS in malignant mesothelioma (MM) cells. Over-expression of TAP1 in MM cells sensitised them to apoptosis by low doses of alpha-TOS which were sub-apoptotic for the parental cells. Apoptosis induced in TAP1-over-expressing cells was mitochondria- and caspase-dependent, as suggested by dissipation of mitochondrial trans-membrane potential and inhibition by zVAD-fmk, respectively. Binding assays showed affinity of alpha-TOS for TAP1. Finally, TAP1 over-expressing cells accumulated alpha-TOS at higher levels compared to their normal counterparts. We suggest that TAP1 may act as an intracellular shuttle for alpha-TOS, promoting apoptosis initiated by this vitamin E analogue, as shown here for MM cells.
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld, Australia. j.neuzil@griffith.edu.au
Jiri
J
Neuzil
Lan-Feng
LF
Dong
Xiu-Fang
XF
Wang
Jean-Marc
JM
Zingg
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008074:Lipoproteins / Q000502:physiology*; D008564:Membrane Potentials; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology; D024505:Tocopherols; D015534:Trans-Activators / Q000502:physiology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008074:Lipoproteins; C432422:SEC14L2 protein, human; D015534:Trans-Activators; D014810:Vitamin E; D020169:Caspases; D024505:Tocopherols