Suppression of NAF-1 in Breast Cancer Cells Reduces their Tumorigenicity by Interfering with Cellular Iron Distribution and Metabolism and Ensuing ROS Formation and Apoptosis

Nutrient autophagy factor 1 (NAF-1) is an iron-sulfur protein found on the outer mitochondrial membrane and the ER. Recent studies highlighted an important role for NAF-1 in regulating autophagy via interaction with BCL-2. We recently reported that the level of NAF-1 is elevated in cancer cells and that NAF-1 is required for tumor growth. Here we report that shRNA suppression of NAF-1 results in the activation of apoptosis in xenograft tumors and cancer cells grown in culture. Suppression of NAF-1 resulted in a depletion in the cytosolic iron pool, facilitated uptake of iron, and accumulation of iron and ROS in mitochondria, a shift to glycolysis and glutaminolysis, and the activation of cellular stress pathways associated with HIF1a, AMPK and mTOR. Suppression of NAF-1 in breast cancer cells appears therefore to reduce their tumorigenicity by interfering with cellular iron distribution and energy metabolism resulting in the activation of apoptosis. Overall design: Examination of the effect of suppression of NAF-1 in the breast cancer cell line MCF-7. Two sample types were analyzed, MCF-7 suppressed for NAF-1 and MCF-7 Empty vector control, three replicates for each.

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Holt SH, Darash-Yahana M, Sohn YS, Song L, Karmi O, Tamir S, Michaeli D, Luo Y, Paddock ML, Jennings PA, Onuchic JN, Azad RK, Pikarsky E, Cabantchik IZ, Nechushtai R, Mittler R