The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.
Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
Heather
H
Venant
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
Mehrdad
M
Rahmaniyan
Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
E Ellen
EE
Jones
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
Ping
P
Lu
Department of Hematology and Oncology, Medical University of South Carolina, Charleston, South Carolina.
Michael B
MB
Lilly
Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
Elizabeth
E
Garrett-Mayer
Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
Richard R
RR
Drake
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
Jacqueline M
JM
Kraveka
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania.
Charles D
CD
Smith
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. johnsocv@musc.edu.
Christina
C
Voelkel-Johnson
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
D000218:Adamantane; D002518:Ceramides; D010088:Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011725:Pyridines; C109343:dihydroceramide; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide; C108138:dihydroceramide desaturase; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase