title: Blockade of paclitaxel-induced thymidine phosphorylase expression can accelerate apoptosis in human prostate cancer cells.
abstract: Recently, survival benefit by chemotherapy using paclitaxel (PTX) and the induction of thymidine phosphorylase (TP) by PTX have been reported in several solid tumors. On the other hand, TP confers antiapoptotic effect on tumor cells through inhibition of caspase-8 activation in vitro. On the basis of these previous observations, we hypothesized that (a) TP can be induced after PTX treatment in human prostate cancer (PC) and (b) blockade of PTX-induced TP expression can enhance the apoptotic processes in human PC cells. PTX was used to find TP expression in all eight hormone-refractory PC cases after chemotherapy; however, cleaved caspase-8 was not expressed after chemotherapy in the six hormone-refractory PC cases with strong TP expression. In PC cell lines (PC-3, DU 145, and LNCaP), TP expression after PTX treatment was clearly up-regulated in a dose-dependent manner. Cell viability of PC cell lines treated with PTX and TP antisense was significantly reduced in a time-dependent and dose-dependent manner compared with the PTX treatment alone. Likewise, apoptotic index of PC cells treated with PTX and TP antisense was significantly increased in comparison with PTX alone. After complete blockade of PTX-induced TP translation by TP antisense transfection, cleaved form of caspase-3 and poly(ADP-ribose) polymerase was increased, and this exaggeration of apoptosis also ran parallel with caspase-8 activation in a PTX dose-dependent manner. However, in PC cell lines treated with TP antisense alone, neither caspase-3 nor poly(ADP-ribose) polymerase was cleaved despite caspase-8 activation. These results indicate that PTX-induced TP up-regulation is associated with decreased caspase-8 activation. This study is the first report showing that blockade of PTX-induced TP expression could exaggerate the processing of apoptosis in PC cells treated with PTX. Our results provide preclinical evidence that TP could be a new molecular target for enhancing the potency of PTX-mediated apoptosis in PC cells.
authors.affiliation: Department of Urology, Biochemistry and Molecular Medicine, and Pathological Laboratories, Shimane University School of Medicine, Izumo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kikuno
authors.forename: Nobuko
authors.initials: N
authors.lastname: Moriyama-Gonda
authors.forename: Tateki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Yoneda
authors.forename: Shinji
authors.initials: S
authors.lastname: Urakami
authors.forename: Masaharu
authors.initials: M
authors.lastname: Terashima
authors.forename: Manabu
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kishi
authors.forename: Kazushi
authors.initials: K
authors.lastname: Shigeno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.forename: Mikio
authors.initials: M
authors.lastname: Igawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011065:Poly(ADP-ribose) Polymerases; D013939:Thymidine Phosphorylase; D017430:Prostate-Specific Antigen; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D017239:Paclitaxel