Transcription levels of invasion-related genes in prostate cancer cells are modified by inhibitors of tyrosine kinase.
Previous reports have shown that genistein and tyrphostin AG-1478, two tyrosine kinase inhibitors (TKIs), exert multiple cellular effects in prostate carcinoma cells, e.g. a reduction in the production of urokinase plasminogen activator (uPA) and its receptor uPAR, and a decrease in the cells' ability to invade an artificial basement membrane. Microarray technology was used to measure alterations in mRNA levels caused by TKI treatment in two prostatic carcinoma cell lines, PC-3 and DU-145. Genistein treatment led to a reduction of at least 50% in 78 genes in PC-3, while 82 were twofold upregulated. In DU-145, the same treatment resulted in a 50% decreased transcript level in 120 genes, and increased expression in 25 genes. Tyrphostin AG-1478 produced a 50% reduction in mRNA levels in 58 genes in DU-145, whereas no alterations were demonstrated using the tyrphostin in PC-3 cells. Among the effects of TKIs, a lowered uPA and uPAR transcription was demonstrated in genistein-treated cells, while a few metalloproteinases (MMPs) were affected. Transcription of various integrin subunits was also downregulated overall. Several alterations in gene transcription were demonstrated in PC-3 and DU-145 after TKI treatment. This knowledge could be of importance in the search for new therapeutic strategies in prostate cancer treatment, and the interplay between the various effects needs to be investigated further.
Skogseth
Haakon
H
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, St. Olav's Hospital, Trondheim, Norway. haakon.skogseth@ntnu.no
Follestad
Turid
T
Larsson
Erik
E
Halgunset
Jostein
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D040081:Protein Array Analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D045726:Metalloproteases; D014568:Urokinase-Type Plasminogen Activator