BNIP3 regulates AT101 [(-)-gossypol] induced death in malignant peripheral nerve sheath tumor cells.
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-1α induced expression of the atypical BH3-only protein BNIP3. These effects were mediated by intracellular iron chelation, a previously unreported mechanism of AT101 cytotoxicity.
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Niroop
N
Kaza
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Latika
L
Kohli
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Christopher D
CD
Graham
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Barbara J
BJ
Klocke
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Steven L
SL
Carroll
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Kevin A
KA
Roth
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009442:Neurilemmoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; C090121:BNIP3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D007501:Iron; D006072:Gossypol; C028178:gossypol acetic acid