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The mechanisms by which fenretinide and all‐trans RA induces apoptosis and differentiation, respectively in human HCC cells
Author(s) -
Bushue Nathan,
Wan YuJui Yvonne
Publication year - 2010
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.24.1_supplement.965.9
Subject(s) - fenretinide , apoptosis , retinoic acid , autophagy , cancer research , programmed cell death , retinoid , receptor , microbiology and biotechnology , cell culture , chemistry , biology , biochemistry , genetics
Fenretinide [ N ‐(4‐hydroxyphenyl) retinamide] is a synthetic analog of all‐trans retinoic acid (RA). We have previously shown that fenretinide, but not all‐trans RA, induced apoptosis in Huh7 cells, a human hepatocellular carcinoma (HCC) cell line. While previous data shows that both differentiation and apoptosis are mediated through a retinoic acid receptor β (RARβ)‐dependent manner, the mechanisms by which fenretinide and all‐trans RA exert their different roles are not well understood. Our data showed that both chemicals induced RARβ mRNA and protein levels as well as activated ERK1/2 and Akt within 3 hrs. Both chemicals also induced the expression level of LC3. However, the conversion of LC3‐I to LC3‐II, a hallmark of autophagy, was substantially higher in all‐trans RA than fenretinide‐treated cells. In addition, the level of signaling adaptor p62, which is crucial for activation of death receptors and caspase 8‐mediated apoptosis, was significantly lower in all‐trans RA than fenrentinide‐treated Huh7 cells. Consequentially, fenretinide, but not all‐trans RA, caused ROS accumulation in Huh7 cells, which in turn lead to apoptosis. Taken together, the differential autophagy induction and p62 degradation might account for the different effect of all‐trans RA and fenretinide in controlling the survival or death of HCC cells.