Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5506014 | Biochemical and Biophysical Research Communications | 2017 | 7 Pages |
Abstract
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 (20Â 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.
Keywords
nSMaseTSAqRT-PCRSPLSphK1PDMPPTXS1PPPMPSMaseDNRGCsASMaseLC-MS/MSacid sphingomyelinaseSphingosine 1-phosphate lyasesphingosine 1-phosphatesphingomyelinaseneutral sphingomyelinaseacid ceramidaseTrichostatin ADaunorubicinhuman prostate cancer cell linePaclitaxel resistancequantitative reverse transcription polymerase chain reactionPaclitaxelliquid chromatography–tandem mass spectrometryglucosylceramide synthase
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Authors
Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate,