Phthoxazolin A inhibits prostate cancer growth by modulating tumor-stromal cell interactions.
Because stroma in tumor tissues can promote prostate cancer development, modulation of tumor-stromal cell interactions may represent an attractive new strategy for cancer treatment. Here, we report that phthoxazolin A and its analog inthomycin B inhibit the growth of human prostate cancer DU-145 cells by modulating tumor-stromal cell interactions. Using an in vitro coculture system, in which prostate cancer cell growth is upregulated by prostate stromal cells (PrSC), we found that phthoxazolin A and inthomycin B strongly inhibited the growth of DU-145 cells when in coculture with PrSC compared to DU-145 cells cultured alone. Although PrSC consist of both fibroblasts and myofibroblasts, phthoxazolin A and inthomycin B inhibited the expression of smooth muscle alpha-actin, a myofibroblast marker, without affecting vimentin and beta-actin expression. Because myofibroblasts secrete various factors that can promote tumor cell growth, we examined whether the inhibitory compounds affected the secretion of such factors from PrSC. Proteomic analysis and reverse transcription-polymerase chain reaction revealed that phthoxazolin A and inthomycin B inhibited the expression of several insulin-like growth factor binding proteins and insulin-like growth factor (IGF)-I by PrSC. Transforming growth factor-beta1 increased myofibroblast numbers and IGF-I levels in PrSC. Phthoxazolin A inhibited transforming growth factor-beta1 activity without altering phosphorylation of the downstream molecule smad2. Furthermore, conditioned medium from phthoxazolin A-treated PrSC failed to increase the phosphorylation of IGF-IR and Akt in DU-145 cells. Taken together, our results suggested that phthoxazolin A acts as a small-molecule modulator of tumor-stromal cell interactions that can indirectly suppress prostate cancer cell growth through inhibition of IGF-I production by PrSC.
Kawada
Manabu
M
Drug Development Unit, Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan. kawadam@bikaken.or.jp
Inoue
Hiroyuki
H
Usami
Ihomi
I
Ikeda
Daishiro
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D005233:Fatty Alcohols / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology
D000970:Antineoplastic Agents; D005233:Fatty Alcohols; D010080:Oxazoles; D053284:Polyunsaturated Alkamides; D053773:Transforming Growth Factor beta1; C066102:phthoxazolin; D007334:Insulin-Like Growth Factor I