PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation

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Lung cancer, the leading cause of cancer mortality worldwide, is often diagnosed at late stages and responds poorly to conventional therapies, including chemotherapy and irradiation. A great majority of lung tumors are defective in the p53 pathway, which plays an important role in regulating apoptotic response to anticancer agents. PUMA was identified as an essential mediator of DNA damage-induced and p53-dependent apoptosis. In this study, we investigated the regulation of PUMA by anticancer agents and the therapeutic effects of PUMA in lung cancer cells. We first examined the expression of PUMA in lung cancer cells with different p53 status treated with chemotherapeutic agents. We found that the induction of PUMA by these agents is abolished in p53-deficient lung cancer cells. An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents or γ-irradiation, was used to treat lung cancer cells. PUMA expression resulted in potent growth suppression and apoptosis in lung cancer cells. Low-dose of Ad-PUMA significantly sensitized lung cancer cells to a variety of chemotherapeutic agents and γ-irradiation through induction of apoptosis. These effects of PUMA are mediated by enhanced caspase activation and release of mitochondrial cytochrome C and AIF into the cytosol. We also compared the growth inhibitory effects of PUMA on cancer and normal/non-transformed cells, as well as the efficacy of PUMA and p53 in suppressing lung cancer cell growth. Our results indicated that PUMA is selectively toxic to cancer cells, and more efficient than p53 in suppressing lung cancer cell growth. Furthermore, Ad-PUMA was also found to effectively suppress xenograft tumor growth through induction of apoptosis. Our results indicate that PUMA is an important modulator of therapeutic responses of lung cancer cells and is potentially useful as a sensitizer in lung cancer therapy.