High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation.
Although most of pharmacological therapies for cancer utilize the apoptotic machinery of the cells, the available anti-cancer drugs are limited due to the ability of prostate cancer cells to escape from the anti-cancer drug-induced apoptosis. A human prostate cancer cell line PC3 is resistant to camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of sphingosine kinase (SPHK) and sphingosine 1-phosphate (S1P) receptor in CPT-resistant PC3 and -sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1, and also elevated expression of S1P receptors, S1P(1) and S1P(3), as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA and inhibition of S1P receptor signaling by pertussis toxin in PC3 cells induced significant inhibition of cell growth, suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/S1P signaling by induction of both SPHK1 enzyme and S1P(1)/S1P(3) receptors. These findings strongly suggest that high expression and up-regulation of SPHK1 and S1P receptors protect PC3 cells from the apoptosis induced by CPT.
Akao
Yukihiro
Y
Gifu International Institute of Biotechnology, Kakamigahara 504-0838, Japan. yakao@giib.or.jp
Banno
Yoshiko
Y
Nakagawa
Yoshihito
Y
Hasegawa
Nobuko
N
Kim
Tack-Joong
TJ
Murate
Takashi
T
Igarashi
Yasuyuki
Y
Nozawa
Yoshinori
Y
D000970:Antineoplastic Agents / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099157:Sphingosine Kinase
D000970:Antineoplastic Agents; D002166:Camptothecin; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase