Inhibition of the Ras-Net (Elk-3) pathway by a novel pyrazole that affects microtubules.
Net (Elk-3/SAP-2/Erp) is a transcription factor that is phosphorylated and activated by the Ras-extracellular signal-regulated kinase (Erk) signaling pathway and is involved in wound healing, angiogenesis, and tumor growth. In a cell-based screen for small molecule inhibitors of Ras activation of Net transcriptional activity, we identified a novel pyrazole, XRP44X. XRP44X inhibits fibroblast growth factor 2 (FGF-2)-induced Net phosphorylation by the Ras-Erk signaling upstream from Ras. It also binds to the colchicine-binding site of tubulin, depolymerizes microtubules, stimulates cell membrane blebbing, and affects the morphology of the actin skeleton. Interestingly, Combretastin-A4, which produces similar effects on the cytoskeleton, also inhibits FGF-2 Ras-Net signaling. This differs from other classes of agents that target microtubules, which have either little effect (vincristine) or no effect (docetaxel and nocodazole) on the Ras-Net pathway. XRP44X inhibits various cellular properties, including cell growth, cell cycle progression, and aortal sprouting, similar to other molecules that bind to the tubulin colchicine site. XRP44X has the potentially interesting property of connecting two important pathways involved in cell transformation and may thereby represent an interesting class of molecules that could be developed for cancer treatment.
Wasylyk
Christine
C
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Sante et de la Recherche Medicale/Université Louis Pasteur, Illkirch Cedex, France. boh@igbmc.u-strasbg.fr
Zheng
Hong
H
Castell
Christelle
C
Debussche
Laurent
L
Multon
Marie-Christine
MC
Wasylyk
Bohdan
B
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D011720:Pyrazoles / Q000378:metabolism* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D000199:Actins; D000970:Antineoplastic Agents; C527883:Elk3 protein, human; C086924:Elk3 protein, mouse; D015513:Oncogene Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011720:Pyrazoles; D014157:Transcription Factors; C527882:XRP44X compound