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Abstract
The association of circulating lipids with clinical outcomes of drug-resistant castration-resistant prostate cancer (CRPC) is not fully understood. Very few studies suggest links between lipid synthesis and poor prognosis. Such a finding has the potential to significantly enhance treatment strategies. Towards this goal, we utilized a multi-platform lipidomics approach to determine differences in the lipidome in diverse in vitro models of prostate cancer. This approach was based on recent clinical studies demonstrating an association between plasma lipids and CRPC patient prognosis . However, it is not known if such changes in patients can be recapitulated in in vitro models. We addressed this question using non-cancerous, hormone sensitive, CRPC and drug resistant prostate cell lines combined with an untargeted shotgun approach (ESI-MS) and quantitative HPLC- ESI-Orbitrap-MS lipidomic analysis. This approach identified distinct metabolite features that varied significantly across all samples analyzed. Among the individual classes identified, phosphatidylcholine (PC), lysophosphatidylcholine (LPC), oxidized lysophosphatidylcholine (OxLPC), phosphatidylethanolamines (PE), lysophosphatidylethanolamine (LPE), oxidized phosphatidylethanolamines OxLPE, sphingomyelin (SM), plasmalogen, and triacylglycerides (TAG) were all determined to be elevated in prostate cancer cells and corresponding media, as compared to non-cancer prostate cells. PC levels increased in two hormone-sensitive cell lines (22RV1 and LNCaP), two castration-resistant cell lines (DU-145 and PC-3), and two Docetaxel resistant cell lines (DU145-DR and PC3-Rx) when compared to non-cancerous RWPE1 and PNT2 cells. PC (36:1), as identified by exact mass and confirmed by MS/MS spectra, was significantly increased in both Docetaxel resistant PC-3 (PC3-Rx) and Docetaxel resistant (DU145-DR) cells. PC (36:4) was significantly enriched in PC3-Rx cells, compared to PC-3 parent controls. LPC and oxidized phosphatidylcholine (OxPC) lipids were significantly elevated in PC-3 cells when compared to non-cancerous and hormone-sensitive cells. However, there was a significant enrichment of OxPC in the media of PC3-Rx and DU145-DR cells, as compared to media from parent control and non-cancerous cells. OxLPC was also significantly enriched in media from PC-3, PC3-Rx cells as compared to non-cancerous cells. PE lipid species showed significant enrichment in 22RV1, DU-145 and PC3-Rx cells as compared to non-cancerous cells. PE (38:4) was significantly enriched in PC3-Rx cells, compared to PC-3 parent control. LPE lipids were enriched in PC-3 cells as compared to hormone-sensitive and normal cells. LPE levels were also enriched in media from DU145-DR cells, as compared to parent control cells. Oxidized phosphatidylethanolamine (OxPE) was enriched in PC-3 and PC3-Rx cells as compared to control cells. Sphingomyelins (SM) were enriched in PC3-Rx cells as compared to PC-3 parent control and normal cells. Triacylglycerides (TAG) were enriched in PC3-Rx cells as compared to parent and normal control cells. OxTAG were enriched in media from DU145-DR cells as compared to DU145-DR cells. Plasmalogen lipid species were enriched in both drug resistant cells as compared to non-resistant cell lines. These data demonstrate that the lipidomic profile of Docetaxel resistant prostate cancer cells lines and media significantly differs from non-docetaxel resistant cells as well as non-cancerous prostate cells. The data suggest that the lipidomic profile of prostate cancer cells recapitulate the lipidomic profiles seen in the plasma of prostate cancer patients. As such, these cells will be valuable models for understanding molecular mechanisms that alter lipid synthesis in Docetaxel resistant prostate cancer. These data may also aid in the development of biomarkers for early detection of Docetaxel resistant prostate cancer, giving rise to more personalized treatment options for patients.