Abstract
Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.
Highlights
Ovarian cancer is the fifth leading cause of cancer-related deaths and the leading cause of death among women with gynecological malignancies
Progress has been made in understanding the biology of ovarian cancer, progress in treating patients with this tumor type has been equivocal
The mechanism by which this sensitization occurs is thought to be through the induction of ceramide-mediated endoplasmic reticulum (ER) stress or lysosome-associated membrane glycoprotein 2 (LAMP2)-dependent autophagic flux
Summary
Ovarian cancer is the fifth leading cause of cancer-related deaths and the leading cause of death among women with gynecological malignancies. The mechanism by which this sensitization occurs is thought to be through the induction of ceramide-mediated ER stress or lysosome-associated membrane glycoprotein 2 (LAMP2)-dependent autophagic flux Consistent with this hypothesis, drug-resistant SKOV3-TR ovarian cancer and ADR/RES breast cancer cells express relatively high levels of CERT, and silencing of COL4ABP sensitizes these cell lines to paclitaxel-induced cell death[7,28,32]. Despite incomplete characterization of function and mechanism, in vitro and preclinical in vivo data document that the SPHK2-specific inhibitor ABC294640 has been shown to inhibit proliferation of tumor cells or tumors more effectively or than agents that target SPHK1 in several tumor models, including ovarian[122], multiple myeloma[123], lung[124], kidney[58], breast[58,125], prostate[126], and pancreatic cancers[127]. We suggest that therapeutics that promote ceramide accumulation by any of several pathways have broad translational potential
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