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-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.

AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells

“…The mRNA levels of BNIP3 and BNIP3L were strongly upregulated upon treatment with AT 101 in U87MG, MZ-54 and U343 cells ( Figure 6(a,b)). These data are consistent with another study showing upregulation of BNIP3 upon AT 101 treatment [39]. We also investigated the expression of the selective cargo receptor SQSTM1/p62 (sequestome 1), which has been described to participate in the PINK1-PRKN mitophagy pathway [33].…”

Preparation of novel (-)-gossypol nanoparticles and the effect on growth inhibition in human prostate cancer PC-3 cells in vitro

“…In the present study, (-)-gossypol nanoparticles were shown to effectively inhibit the growth of prostate cancer PC-3 cells in vitro , with their toxicity similar to that of free (-)-gossypol. In a previous study ( 18 ), the slow-release ability of (-)-gossypol was revealed, with a potential release of ~40% in 48 h. At the same dose, (-)-gossypol nanoparticles release less compared with free (-)-gossypol, indicating that the antitumor effect of (-)-gossypol nanoparticles is stronger than that of free (-)-gossypol. This may result from the ability of nanoparticles to penetrate into cells through cell endocytosis, which is not possible for small-molecule drugs ( 19 , 20 ).…”

Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

“…It was previously established that Hif-1α is a transcriptional regulator of Bnip3 [ 26 ]. Recently, AT-101 (modified enantiomer of gossypol) was shown to stabilize Hif-1α protein without any increase in mRNA levels [ 27 ]. Furthermore, under normoxic conditions Hif-1α is spontaneously hydroxylated by prolyl hydroxylase, an enzyme that requires oxygen and iron to perform its enzymatic activity.…”

“…Furthermore, under normoxic conditions Hif-1α is spontaneously hydroxylated by prolyl hydroxylase, an enzyme that requires oxygen and iron to perform its enzymatic activity. AT-101 treatment caused intracellular iron chelation and resulted in accumulation of Hif-1α in nerve sheath tumor cells [ 27 ]. In our study, Sabutoclax-induced Hif-1α, Bnip3 and LC3-II and expression was blocked significantly when the media was supplemented with iron in the form of ferric citrate ( Supplementary Fig.…”