Modulation of the sphingolipid rheostat is involved in paclitaxel resistance of the human prostate cancer cell line PC3-PR.
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.
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Yuka
Y
Aoyama
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Sayaka
S
Sobue
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Naoki
N
Mizutani
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Chisato
C
Inoue
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Yoshiyuki
Y
Kawamoto
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Yuji
Y
Nishizawa
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan.
Masatoshi
M
Ichihara
Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, 466-0064, Japan.
Mamoru
M
Kyogashima
Department of Microbiology and Molecular Biology, Nihon Pharmaceutical University, Saitama, 362-0806, Japan.
Motoshi
M
Suzuki
Tokai Gakuin University, Kakamigahara, 504-8511, Japan.
Yoshinoti
Y
Nozawa
College of Life and Health Sciences, Chubu University, Kasugai, 487-8501, Japan. Electronic address: murate@isc.chubu.ac.jp.
Takashi
T
Murate
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008297:Male; D008614:Meperidine / Q000031:analogs & derivatives / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005964:Glucosyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D008614:Meperidine; D009025:Morpholines; D017239:Paclitaxel; D017853:Phosphotransferases (Alcohol Group Acceptor); D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; D000099157:Sphingosine Kinase; C108209:SP1 protein, human; C026733:4-propionyloxy-4-phenyl-N-methylpiperidine; C033110:RV 538; C023246:ceramide glucosyltransferase; C112980:acid sphingomyelinase-1; C491484:SMPD3 protein, human
Glucosylceramide synthase; Human prostate cancer cell line; Paclitaxel resistance; SPHK1; Sphingolipid rheostat; Sphingomyelinase