The Onus of Sphingolipid Enzymes in Cancer Drug Resistance

Abstract

Chemotherapy resistance, inherent or acquired, represents a serious barrier to the successful treatment of cancer. Although drug efflux, conducted by plasma membrane-resident proteins, detoxification enzymes, cell death inhibition, and DNA damage repair are ensemble players in this unwanted biology, a full understanding of the many in concert molecular mechanisms driving drug resistance is lacking. Recent discoveries in sphingolipid (SL) metabolism have provided significant insight into the role of these lipids in cancer growth; however, considerably less is known with respect to SLs and the drug-resistant phenotype. One exception here is enhanced ceramide glycosylation, a hallmark of multidrug resistance that is believed responsible, in part, for diminishing ceramides tumor-suppressor potential. This chapter will review various aspects of SL biology that relate to chemotherapy resistance and extend this topic to acknowledge the role of chemotherapy selection pressure in promoting dysregulated SL metabolism, a characteristic in cancer and an exploitable target for therapy.

Keywords: Ceramide; Chemotherapy (drug) resistance; Glucosylceramide synthase; Sphingolipid.