The ceramide-sphingosine-1-phosphate rheostat as a therapeutic target in endocrine and chemotherapy resistant breast cancer
Description
Despite significant improvements in the diagnosis and treatment of breast carcinoma over the past several decades, resistance and toxicity in response to therapy remains the primary cause of breast cancer treatment failure today. Recent studies have indicated that aberrant sphingolipid metabolism resulting in a decrease in endogenous ceramides and increase in sphingosine-1-phosphate (S1P) is an important mediator of both chemo- and endocrine therapy-resistance. The balance between these lipids is tightly regulated by the enzyme sphingosine kinase, which converts pro-apoptotic, antiproliferative ceramide into its pro-survival and mitogenic metabolite S1P. The term Ceramide-S1P rheostat, refers to the concept that it is the relative ratio of ceramide to S1P that determines cell fate. Therefore, sphingosine kinase has been proposed to be a 'switch' turning cells from an anti-growth state into a proliferative one. In many cancers, increased expression and activity of sphingosine kinase alters the rheostat, resulting in malignancy. Similarly, decreased ceramide generation in response to chemotherapy and increased activity of sphingosine kinase has been shown to be a key mechanism of drug resistance in breast cancer Utilizing a number of ceramide analogs and sphingosine kinase inhibitors, we examined the effects of targeting the Ceramide-S1P rheostat in the treatment of drug sensitive and drug resistant breast cancer. Our results indicate that modifying the amide bond of short chain ceramides can increase their potency resulting in enhanced antiviability and anti-proliferative effects in both chemoresistant and endocrine therapy resistant breast cancers. These ceramide analogs altered the sphingolipid profile and induced apoptosis to exert their effects and exhibited additive anti-viability properties when using in combination with current clinical chemotherapeutics, such as etoposide and doxorubicin. These results suggest that using short-chain ceramide analogs have therapeutic potential in treating drug resistant breast cancer Two novel sphingosine kinase-2 inhibitors, SKI-II and ABC294640, were shown to block formation and downstream signaling of S1P. These inhibitors exhibit low-micromolar efficacy in viability, clonogenic survival and proliferation assays in drug resistant breast cancer. Furthermore, both inhibitors can induce apoptosis through the mitochondrial pathway in a wide variety of breast cancer cell lines. In ER-positive breast cancer, both SKI-II and ABC294640 can directly bind the estrogen receptor in an antagonistic fashion and decrease ER transcriptional activity to block estrogen signaling both in vitro and in vivo. Furthermore, in both ER-positive and ER-negative cancer, these drugs diminish NF-kappaB transcription factor signaling through blockade of p65 phosphorylation, resulting in decreased p65 transcriptional activity. Finally, using xenograft animal models, the inhibitor ABC294640 was shown to decrease drug sensitive, endocrine therapy resistant and chemotherapy resistant tumor growth in vivo. Taken together, these results indicate that targeting sphingosine kinase is a viable and promising approach in the treatment of drug sensitive and refractory breast cancer