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Lipid Rafts and Nonrafts Mediate Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptotic and Nonapoptotic Signals in Non–Small Cell Lung Carcinoma Cells

Departments of ¹ Pathology and Laboratory Medicine and ² Hematology and Oncology and ³ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; and ⁴ Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

Requests for reprints: Chunhai Hao, Department of Pathology and Laboratory Medicine, Emory University, 1365-C Clifton Road, Atlanta, GA 30322. Phone: 404-778-4776; Fax: 404-778-5550; E-mail: chao{at}emory.edu or Norman M. Kneteman, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada T6G 2B7. E-mail: nkneteman{at}chaa.ab.ca.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is capable of inducing apoptosis in non–small cell lung carcinoma (NSCLC). However, many of the human NSCLC cell lines are resistant to TRAIL, and TRAIL treatment of the resistant cells leads to the activation of nuclear factor-B (NF-B) and extracellular signal–regulated kinase 1/2 (ERK1/2). TRAIL can induce apoptosis in TRAIL-sensitive NSCLC cells through the induction of death-inducing signaling complex (DISC) assembly in lipid rafts of plasma membrane. In the DISC, caspase-8 is cleaved and initiates TRAIL-induced apoptosis. In contrast, TRAIL-DISC assembly in the nonraft phase of the plasma membrane leads to the inhibition of caspase-8 cleavage and NF-B and ERK1/2 activation in TRAIL-resistant NSCLC cells. Receptor-interacting protein (RIP) and cellular Fas-associated death domain–like interleukin-1ß–converting enzyme-inhibitory protein (c-FLIP) mediates the DISC assembly in nonrafts and selective knockdown of either RIP or c-FLIP with interfering RNA redistributes the DISC from nonrafts to lipid rafts, thereby switching the DISC signals from NF-B and ERK1/2 activation to caspase-8–initiated apoptosis. Chemotherapeutic agents inhibit c-FLIP expression, thereby enhancing the DISC assembly in lipid rafts for caspase-8–initiated apoptosis. These studies indicate that RIP and c-FLIP–mediated assembly of the DISC in nonrafts is a critical upstream event in TRAIL resistance and thus targeting of either RIP or c-FLIP may lead to the development of novel therapeutic strategies that can overcome TRAIL resistance in human NSCLC. [Cancer Res 2007;67(14):6946–55]

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