期刊
MOLECULAR CANCER THERAPEUTICS
卷 6, 期 8, 页码 2249-2260出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-06-0782
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- NCI NIH HHS [R01CA77612] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061656-03, R01 DK061656-04, R01 DK061656-02, R01 DK061656, R01 DK061656-05, R01 DK061656-01, R01DK61615] Funding Source: Medline
- NIGMS NIH HHS [R01GM39561] Funding Source: Medline
Lysophosphatidic acid receptors stimulate a G alpha(12/13)/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-lucif erase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by G alpha(12)Q231L, G alpha(13)Q226L, RhoA-G G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (< 1 mu mol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SKMel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis; of the metastasis-prone, Rho C-overex pressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the G alpha(i)-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer.
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