Abstract— Resistance of colorectal cancer cells to paclitaxel- induced apoptosis is largely mediated by the activation of MEK/ERK signalling pathway. Inhibition of MEK/ERK pathway sensitized CRC cells to paclitaxel-induced apoptosis by down-regulation of GRP78

Resistance of colorectal cancer cells to paclitaxelinduced apoptosis is largely mediated by the activation of MEK/ERK signalling pathway. Inhibition of MEK/ERK pathway sensitized CRC cells to paclitaxel-induced apoptosis by down-regulation of GRP78. In the present study, we report that induction of apoptosis by paclitaxel when GRP78 is down-regulated involves activation of the caspase cascade. In cells, where GRP78 is inhibited, paclitaxel induced activation of caspase-3, caspase-4, and caspase-9. Caspase-4 seemed to be the apical caspase in that caspase-4 activation occurred before activation of caspase-9 and caspase-3. Moreover, activation of caspase-4 was upstream of the mitochondria and its inhibition led to the inhibition of mitochondrial membrane permeability (MMP) and caspase-9 activation. Furthermore, co-immunoprecipitation studies revealed that GRP78 is physically associated with caspase-4 before and after treatment with paclitaxel. These results indicate that GRP78 might be a novel mechanism underlying resistance of CRC cells to microtubule-targeting drugs by binding to and inhibition of caspase4. Combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes in treatment of CRC.