Modulation of the sphingolipid rheostat is involved in paclitaxel resistance of the human prostate cancer cell line PC3-PR

• Published in: Biochemical and biophysical research communications 2017-04, Vol.486 (2), p.551-557
• Main Authors: Aoyama, Yuka, Sobue, Sayaka, Mizutani, Naoki, Inoue, Chisato, Kawamoto, Yoshiyuki, Nishizawa, Yuji, Ichihara, Masatoshi, Kyogashima, Mamoru, Suzuki, Motoshi, Nozawa, Yoshinoti, Murate, Takashi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Antineoplastic Agents, Phytogenic - pharmacology; Cell Line, Tumor; CELL PROLIFERATION; Cell Proliferation - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme Inhibitors - pharmacology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic - drug effects; Glucosylceramide synthase; Glucosyltransferases - antagonists & inhibitors; Glucosyltransferases - genetics; Glucosyltransferases - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Human prostate cancer cell line; Humans; INHIBITION; K562 Cells; Male; Meperidine - analogs & derivatives; Meperidine - pharmacology; MODULATION; Morpholines - pharmacology; NEOPLASMS; Paclitaxel - pharmacology; Paclitaxel resistance; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; PROSTATE; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Sphingolipid rheostat; Sphingolipids - metabolism; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelinase; SPHK1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.03.084

Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment. Western blotting revealed that PC3-PR cells expressed higher levels of sphingosine kinase 1 (SPHK1) and glucosylceramide synthase (GCS) but lower levels of acid sphingomyelinase (ASMase) and neutral sphingomyelinase 2 than did PC3 cells. Inhibition of SPHK1 using siRNA or a pharmacological inhibitor decreased S1P levels in PC3-PR cells and inhibited proliferation in the presence or absence of PTX, suggesting that SPHK1 is at least partially responsible for PTX resistance. Similarly, GCS inhibitors (PDMP and PPMP) increased cellular ceramides and suppressed the proliferation of PC3-PR. However, inhibition of proteasome function or histone deacetylase activity increased SMase and ceramide levels and suppressed PC3-PR proliferation. These results suggest that modulation of metabolic enzyme expression and alteration of the sphingolipid rheostat protects cancer cells against PTX. •S1P levels are higher in paclitaxel-resistant PC3-PR cells than in PC3 cells.•SPHK1 and GCS expression is higher in PC3-PR cells than in PC3 cells.•ASMase and NSMase2 expression is lower in PC3-PR cells than in PC3 cells.•SPHK1 and GCS inhibition blocks proliferation and increases ceramides in PC3-PR cells.•MG132 and TSA induce ASMase and NSMase2 expression and increase cellular ceramides.