Abstract
Mcl-1 is an antiapoptotic member of the Bcl-2 family frequently upregulated in non-small cell lung carcinoma (NSCLC). We now report the physiological significance of an interaction between Mcl-1 and the mitochondrial outer membrane-localized voltage-dependent anion channel (VDAC) in NSCLC cell lines. Mcl-1 bound with high affinity to VDAC1 and 3 isoforms but only very weakly to VDAC2 and binding was disrupted by peptides based on the VDAC1 sequence. In A549 cells, reducing Mcl-1 expression levels or application of VDAC-based peptides limited Ca2+ uptake into the mitochondrial matrix, the consequence of which was to inhibit reactive oxygen species (ROS) generation. In A549, H1299 and H460 cells, both Mcl-1 knockdown and VDAC-based peptides attenuated cell migration without affecting cell proliferation. Migration was rescued in Mcl-1 knockdown cells by experimentally restoring ROS levels, consistent with a model in which ROS production drives increased migration. These data suggest that an interaction between Mcl-1 and VDAC promotes lung cancer cell migration by a mechanism that involves Ca2+-dependent ROS production.
Highlights
Bcl-2 family members are frequently upregulated in cancer, determining if and how these non-canonical interactions confer survival or other advantages to the cancer cell, will be an important step toward identifying new therapeutic targets
Similar to the findings reported previously for Bcl-xL,[7] Mcl-1 bound more strongly to VDAC1 compared with VDAC3, and only weakly bound to VDAC2 (Figure 1a)
Compared with the amounts of Mcl-1 and Bcl-xL detected in the input lysate, VDAC1 appeared to pull down a greater proportion of the available Mcl-1 relative to Bcl-xL, suggesting that VDAC1 favors binding to Mcl-1 over Bcl-xL
Summary
Bcl-2 family members are frequently upregulated in cancer, determining if and how these non-canonical interactions confer survival or other advantages to the cancer cell, will be an important step toward identifying new therapeutic targets. One such interaction is with the outer mitochondrial membrane-localized voltage-dependent anion channel (VDAC), a porin channel with three isoforms that serves as a major diffusion pathway for ions and metabolites,[3] and whose gating properties are affected by either Bcl-2 or Bcl-xL binding.[4,5,6]. While excessive ROS levels are toxic, sub-lethal production serves an important signaling function, in cancers, were ROS promote cell proliferation, migration and invasion.[11,12,13,14,15] A primary source of ROS are the mitochondria, and a number of mitochondrial signaling pathways are known to be remodeled and contribute to elevated ROS in cancer cells, including those involved in regulating the electron transport chain (ETC) function and metabolic activity.[11,16,17,18]
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