In contrast to altered lipid metabolism in cancer cells that promote their proliferation, drug-induced changes in lipid metabolism may help to fight cancers. One such example is ceramide-induced inhibition of proliferation of cancer cells. We have recently determined that doxorubicin, an extensively used chemotherapeutic reagent, induces synthesis of ceramide, which in turn inhibits proliferation of cancer cells through proteolytic activation of a transcription factor called CREB3L1. Unlike typical transcription factors, CREB3L1 is synthesized as a membrane-bound precursor, just like SREBP studied extensively in our department. In cells treated with doxorubicin, CREB3L1 is cleaved by the same proteases that cleave SREBP. This proteolysis releases the NH2-terminal domain of the protein from membranes, allowing it to enter nucleus where it activates transcription of genes that inhibit progression of cell cycle (Fig. 2). These observations suggest that CREB3L1 is a key determinant for cellular response to doxorubicin. Indeed, we observed that cancer cells expressing CREB3L1 were much more sensitive to doxorubicin than those that did not express the protein. We are currently trying to determine whether CREB3L1 expression can be used clinically as a biomarker to identify cancer patients who are most likely to benefit from doxorubicin treatment.
While effective in treating certain cancers, the application of doxorubicin is limited by its cardiac toxicity. Since we now know that doxorubicin functions through CREB3L1, we will screen for compounds that activate CREB3L1 in the absence of cardiac toxicity. Identification of such compound may dramatically improve doxorubicin-mediated chemotherapy.