Heme oxygenase-1-mediated apoptosis under cadmium-induced oxidative stress is regulated by autophagy, which is sensitized by tumor suppressor p53.
Heme oxygenase-1 (HO-1) is a stress-inducible cytoprotective enzyme. It is often overexpressed in different types of cancers and promotes cell survival. However, the role of HO-1 and the underlying molecular mechanism of cadmium (Cd)-induced oxidative stress in cancer cells remain undefined. Here we show that the role of HO-1 under Cd-induced oxidative stress is dependent upon autophagy, which is sensitized by the tumor suppressor p53. The sensitivity to Cd was 3.5- and 14-fold higher in p53-expressing YD8 and H460 cells than in p53-null YD10B and H1299 cells, respectively. The levels of p53 in YD8 and H460 cells decreased in a Cd concentration-dependent manner, which was inhibited by pretreatment with N-acetylcysteine. In both cell lines, Cd exposure resulted in caspase-3-mediated PARP-1 cleavage and the induction of CHOP, LC3-II, and HO-1, which were limited in YD10B and H1299 cells exposed to high concentrations of Cd. Cd exposure to p53-overexpressing YD10B cells enhanced Cd-induced HO-1 and LC3-II levels, whereas genetic knockdown of p53 in YD8 cells resulted in the suppression of Cd-induced levels of HO-1 and LC3-II, indicating that p53 is required in the sensing of HO-1 and induction of autophagy. The inhibition of autophagy using small interfering RNA (siRNA) for the autophagy-related gene atg5 enhanced HO-1, CHOP, and PARP-1 cleavage induced by Cd. However, transfection with HO-1 siRNA increased Cd-induced LC3-II, and suppressed the expression of CHOP and cleavage of PARP-1. Collectively, the role of HO-1 in apoptosis could be modulated by autophagy, which is sensitized by p53 expression in human cancer cell lines.
Department of Anesthesiology and Pain Medicine, Chosun University, Gwangju 501-759, South Korea.
Keum-Young
KY
So
Department of Premedics, School of Medicine, Chosun University, Gwangju 501-759, South Korea. Electronic address: seonh@chosun.ac.kr.
Seon-Hee
SH
Oh
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D002104:Cadmium / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D034622:RNA Interference; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C497249:DDIT3 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D051742:Transcription Factor CHOP; D051547:Heme Oxygenase-1; D000071137:Poly (ADP-Ribose) Polymerase-1; D053148:Caspase 3
Apoptosis; Autophagy; Heme-oxygenase-1; p53