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Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition



Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition



Biochemical and Biophysical Research Communications 420(2): 288-292



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.

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Accession: 036375550

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PMID: 22421218

DOI: 10.1016/j.bbrc.2012.02.151


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