Trap1: mitochondeial homolog of cancer chaperone Hsp90 in regulating mitochondrial fession

Abstract

Cancer is a polygenic disease and emerges from the deregulation of both genetic and epigenetic mechanisms. Two hallmarks of cancer, deregulating cellular energetics and evading apoptosis can be directly associated with mitochondria since mitochondria remain the hot spot for both. Mitochondria exist in a dynamic state between 'fusion' and 'fission' and these states regulate several cellular functions including ATP production. High molecular weight heat shock protein, Hsp90 is identified as a 'cancer chaperone' due to its involvement in regulating the functions of several cancer related signal transduction molecules. However, its mitochondrial homologue, TRAP1 does not show cancer associated molecular interactions like Hsp90, but its enhanced expression in cancer cells did correlate with disease progression. To understand TRAP1 involvement in regulating the mitochondrial dynamics between fusion and fission, we examined TRAP1 over expression in comparison with knockdown. We found that TRAP1 over expression does not kill tumor cells, but induces mitochondrial fission-like structural reorganization. To assess whether or not these structural alterations are comparable with fission,

we

cloned and over expressed fission genes, Fis1, Drp1, and Mff in normal (SRA01 and HEK293T) and metastatic cancer cells (IMR-32) and examined for cell and mitochondrial morphology. TRAP1 over expression alone showed enhanced fission compared to individual fission protein expression suggesting that one or all of the fission proteins requires TRAP1 for their regulation. Tumor cells showed more sensitivity to TRAP1 over expression compared to normal cells indicating tumor selective functions. Preliminary studies with protein-protein interaction suggested that TRAP1 interacts with these proteins however subsequent experiments need to be performed for further confirmation with respect to type of fission protein and mapping of the interacting region. Keywords: Cancer, Mitochondrial dynamics, Heat shock proteins, Hsp90, TRAP1, Mitochondrial fission proteins