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BNIP3 regulates AT101 [(-)-gossypol] induced death in malignant peripheral nerve sheath tumor cells.


ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived sarcomas and are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1). Current treatment modalities have been largely ineffective, resulting in a high rate of MPNST recurrence and poor five-year patient survival. This necessitates the exploration of alternative chemotherapeutic options for MPNST patients. This study sought to assess the cytotoxic effect of the BH3-mimetic AT101 [(-)-gossypol] on MPNST cells in vitro and to identify key regulators of AT101-induced MPNST cell death. We found that AT101 caused caspase-independent, non-apoptotic MPNST cell death, which was accompanied by autophagy and was mediated through HIF-1? induced expression of the atypical BH3-only protein BNIP3. These effects were mediated by intracellular iron chelation, a previously unreported mechanism of AT101 cytotoxicity.

SUBMITTER: Kaza N 

PROVIDER: S-EPMC4019476 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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BNIP3 regulates AT101 [(-)-gossypol] induced death in malignant peripheral nerve sheath tumor cells.

Kaza Niroop N   Kohli Latika L   Graham Christopher D CD   Klocke Barbara J BJ   Carroll Steven L SL   Roth Kevin A KA  

PloS one 20140513 5


Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived sarcomas and are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1). Current treatment modalities have been largely ineffective, resulting in a high rate of MPNST recurrence and poor five-year patient survival. This necessitates the exploration of alternative chemotherapeutic options for MPNST patients. This study sought to assess the cytotoxic effect of the BH3-mimetic AT101 [(-)-go  ...[more]

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