Abstract
Cancer cells require higher levels of ATP for their sustained growth, proliferation, and chemoresistance. Mitochondrial matrix protein, C1qbp is upregulated in colon cancer cell lines. It protects the mitochondria from oxidative stress, by inhibiting the Membrane Permeability Transition (MPT) pore and providing uninterrupted synthesis of ATP. This intracellular interaction of C1qbp could be involved in chemoresistance development. Natural chemosensitizing agent, curcumin has been used in the treatment of multiple cancers. In this current study, we elucidate the role of C1qbp during curcumin induced chemosensitization to doxorubicin resistant colon cancer cells. The possible interaction between C1qbp and curcumin was determined using bioinformatics tools-AutoDock, SYBYL, and PyMol. Intracellular doxorubicin accumulation by fluorimetry and dead cell count was carried out to determine development of chemoresistance. Effect of curcumin treatment and cytotoxicity was measured by MTT and lactate dehydrogenase release. Morphological analysis by phase contrast microscopy and colony forming ability by colonogenic assay were also performed. In addition, Cox-2 could mediate P-glycoprotein upregulation via phosphorylation of c-Jun. Thus, the gene level expression of P-glycoprotein and Cox-2 was also investigated using PCR. Through molecular docking we identified possible interaction between curcumin and C1qbp. We observed development of chemoresistance upon 6th day treatment. Concentration dependent alleviation of chemoresistance development by curcumin was confirmed and was found to reduce gene level expression of P-glycoprotein and Cox-2. Hence, curcumin could interact directly with C1qbp protein and this interaction could contribute to the chemosensiting effect to doxorubicin in colon cancer cells.
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