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Research Articles: Therapeutics, Targets, and Development

Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells

¹ Molecular Biology and Lung Cancer Program and ² Respiratory Immunology and Asthma Program, Lovelace Respiratory Research Institute; ³ Cancer Center, School of Medicine, University of New Mexico, Albuquerque, New Mexico; and ⁴ Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China

Requests for reprints: Yong Lin, Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108. Phone: 505-348-9645; Fax: 505-348-4990. E-mail: ylin{at}lrri.org

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent due to its selectivity in killing transformed cells. However, TRAIL can also stimulate the proliferation and metastasis of TRAIL-resistant cancer cells. Thus, acquired TRAIL resistance during TRAIL therapy would shift the patient's treatment from beneficial to detrimental. In this study, we focused on the acquired TRAIL resistance mechanism and showed that the elevated expression of the antiapoptotic factor cellular FLICE-like inhibitory protein (c-FLIP) and the prosurvival Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) underlie the main mechanism of this type of TRAIL resistance in lung cancer cells. Chronic exposure to TRAIL resulted in lung cancer cell resistance to TRAIL-induced cytotoxicity, and this resistance was associated with the increase in the cellular levels of c-FLIP_L and Mcl-1_L. Overexpresssion of c-FLIP_L suppressed recruitment of caspase-8 to the death-inducing signaling complex, whereas increased Mcl-1_L expression blunted the mitochondrial apoptosis pathway. The elevation of c-FLIP_L and Mcl-1_L expression was due to Akt-mediated stabilization of these proteins in TRAIL-resistant cells. Importantly, suppressing c-FLIP_L and Mcl-1_L expression by RNA interference collectively alleviated acquired TRAIL resistance. Taken together, these results identify c-FLIP_L and Mcl-1_L as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer. [Mol Cancer Ther 2008;7(5):1156–63]

Grant support: National Cancer Institute/NIH grant R03CA125796.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/11/07; revised 2/27/08; accepted 2/29/08.