Anacardic acid induces cell apoptosis associated with induction of ATF4-dependent endoplasmic reticulum stress

• Anacardic acid (AA) inhibits tumor growth in vitro and in vivo.
• AA induces endoplasmic reticulum (ER) stress in vitro and in vivo.
• Induction of ATF4-dependent ER stress contributes to AA-induced tumor cell death.
• Extrinsic and intrinsic apoptotic pathways are involved in AA-induced cell apoptosis.

Anacardic acid (6-pentadecylsalicylic acid, AA), a natural compound isolated from the traditional medicine Amphipterygium adstringens, has been reported to possess antitumor activities. However, its molecular targets have not been thoroughly studied. Here, we report that AA is a potent inducer of endoplasmic reticulum (ER) stress, leading to apoptosis in hepatoma HepG2 and myeloma U266 cells. Induction of ER stress by AA was supported by a dose- and time-dependent increase in expression of the ER signaling downstream molecules, such as GRP78/BiP, phosphorylated eIF2α, ATF4 and CHOP in both HepG2 and U266 cell lines. Blockage of ATF4 expression by siRNA partially inhibited, while knockdown of CHOP expression by siRNA slightly increased AA-induced cell death in these cells. In addition, AA suppressed HepG2 xenograft tumor growth, associated with increased ER stress in vivo. These results suggest that AA induces tumor cell apoptosis associated with ATF4-dependent ER stress.