THE CHICKEN OR THE EGG QUESTION OF OXIDATIVE AND ENDOPLASMIC RETICULUM STRESSES IN CANCER THERAPY

Cellular responses to oxidative and endoplasmic reticulum (ER) stress are among the most evolutionarily conserved pathways within the cell. Tumor cells commonly encounter both ER and oxidative stress due to high levels of metabolism, including increased rates of protein translation. Yet drugs aimed primarily at interference with these stress response pathways comprise only a small portion of currently available anti-neoplastic agents. Moreover, little is known about the interrelating connection between ER stress and oxidative stress caused by these few anticancer drugs. For instance, it is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of ER stress. Here, we report a mechanism underlying the ability of proteasome inhibitor bortezomib (BTZ) to directly induce both oxidative and ER stress in multiple myeloma (MM) cells via transcriptional repression of the gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular redox status and detoxification of reactive oxygen species. Depletion of TXNRD2 to the levels detected in BTZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 levels in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared to cells with depleted TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts the therapeutic effects of BTZ. Our data identifies TXNRD2 as a potential clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress, and ER stress.