Autophagy‐mediated growth inhibition of BH3‐mimetic gossypol in malignant glioma cells (796.2)

Abstract

In the present study, we evaluated the individual IC50 values of a BH3‐mimetic gossypol for its cell growth inhibitory effects in four glioma cell lines with different BRAF mutational statuses. NMC‐G1, and DBTRG‐05MG cell lines are heterozygous for BRAF‐V600E; T98G, and U‐87MG cell lines are homozygous for wild‐type (WT) BRAF. Gossypol induced similar levels of growth inhibition in all of glioma cell lines. However, gossypol exhibited no significant effect on the phosphorylation of MEK‐ERK in all three cell lines regardless of both BRAF mutation and drug resistance, implying that gossypol activity is independent of MEK‐ERK inhibition. Glioma cells were found to be resistant to the apoptosis mediated by gossypol, which caused only a weak increase in G2/M cells. Rather, gossypol resulted in the progressive emergence of autophagic cells in glioma cells, as determined by GFP‐LC3 puncta/cell counts. Further, autophagy inhibition with 3‐methyladenine partially rescued the growth inhibitory effect of gossypol in DBTRG‐05MG cells, suggesting that the pro‐death autophagic processes may be one of the underlying mechanisms for the sensitization of tumor cells toward gossypol. Collectively, our data suggest that gossypol may contribute to a more effective therapeutic strategy for brain tumor patients that are unable to activate apoptosis.