title: Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition.
abstract: Smad7, an inhibitory Smad, acts as a key regulator forming autoinhibitory feedback loop in transforming growth factor-beta (TGF-β) signaling. However, a growing body of evidences suggests that Smad7 is capable of apoptotic function. In the present study, we have demonstrated a proapoptotic function of Smad7 as a negative regulator of survival protein heme oxygenase-1 (HO-1). The HO-1 protein level was elevated in cisplatin-resistant A549 human lung cancer cells and blockade of HO-1 activation sensitized the cells to apoptosis. Interestingly, overexpression of Smad7 decreased HO-1 gene expression and its enzymatic activity. Notably, Smad7 reduced Akt activity and infection with adenovirus expressing a constitutively active form of the Akt reversed the inhibitory effects of Smad7 to HO-1, indicating a negative action mechanism of Smad7 to Akt-HO-1-linked survival pathway. Consistently, Smad7 sensitized A549 cells to cisplatin-induced apoptosis and these effects were dependent on HO-1 and Akt inhibition. Based on these findings, we suggest that targeting Smad7 may be an efficient strategy for overcoming drug-resistance in cancer therapy.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Woo-Kwang
authors.initials: WK
authors.lastname: Jeon
authors.forename: Hey-Young
authors.initials: HY
authors.lastname: Hong
authors.forename: Won-Chan
authors.initials: WC
authors.lastname: Seo
authors.forename: Kyu-Hyoung
authors.initials: KH
authors.lastname: Lim
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Kim
authors.forename: Seo-Young
authors.initials: SY
authors.lastname: Song
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin