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BNIP3 regulates AT101 induced cytotoxicity in MPNST cells
Author(s) -
Kaza Niroop,
Carroll Steven L,
Roth Kevin A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.380.3
Subject(s) - autophagy , programmed cell death , gene knockdown , cancer research , neurofibromatosis , apoptosis , cell , regulator , viability assay , cytotoxicity , biology , microbiology and biotechnology , chemistry , medicine , in vitro , pathology , gene , genetics , biochemistry
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell‐derived sarcomas and a leading cause of mortality in neurofibromatosis type 1 (NF1) patients. Current treatment modalities have been ineffective resulting in a high rate of recurrence and poor five year survival, which necessitates the exploration of novel therapeutic agents. AT101, a BH3 mimetic, has been shown to induce cell death in several cancers and is in phase II clinical trials. The objective of this study was to investigate the molecular mechanisms regulating AT101 induced cytotoxicity in human MPNST cells and to evaluate its chemotherapeutic potential for MPNSTs. AT101 caused a concentration dependent decrease in viability in MPNST cells which was not accompanied by caspase activity. AT101 also induced an increase in autophagic flux and inhibiting induction of autophagy attenuated cell death induced by AT101. Additionally, AT101 caused increased expression of BNIP3, an atypical BH3‐ only protein involved in cell death, along with increased levels of HIF‐1α protein, a transcriptional regulator of BNIP3, in MPNST cells. Moreover, siRNA mediated knockdown of BNIP3 significantly attenuated AT101 induced cell death. In conclusion, AT101 induces an increase in BNIP3 expression and autophagy leading to cell death independent of caspase activation in MPNST cells. This work was supported by grants from NCI (RO1 CA134773).