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A p21 Cip1 ‐dependent autophagic cell death by BH3‐mimetic gossypol in mutant BRAF melanoma cells (796.4)
Author(s) -
Jang GunHee,
Lee Michael
Publication year - 2014
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.28.1_supplement.796.4
Subject(s) - gossypol , apoptosis , programmed cell death , cancer research , mutant , autophagy , melanoma , mitosis , chemistry , mapk/erk pathway , cell growth , cell cycle checkpoint , cell culture , biology , cell cycle , microbiology and biotechnology , biochemistry , signal transduction , gene , genetics
In this study, we described the potential therapeutic effects of BH3‐mimetic gossypol on melanoma cells with acquired resistance to BRAF inhibitors. Gossypol retained its efficacy in BRAF‐V600E melanoma clones with acquired resistance to BRAF inhibitors through a mechanism independent of MEK‐ERK inhibition. Gossypol caused G 2 /M arrest in both BRAF mutant A375P and A375P/Mdr cells with high expression of p21 Cip1 , regardless of their drug resistance. Interestingly, we determined that the lack of gossypol‐induced mitotic arrest in BRAF‐WT‐harboring SK‐MEL‐2 cells was associated with a low level of p21 Cip1 expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol‐sensitive cells and not in the gossypol‐resistant SK‐MEL‐2 cells, which suggests that apoptosis and autophagy can occur simultaneously and act as cooperative partners for the induction of cell death. Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor‐resistant tumors, but a functional p21 Cip1 is a prerequisite for a positive response to its clinical application.