Abstract LB-215: Inhibition of Polo-like kinase 4 as an anti-cancer strategy
| Autor: | Vincent Nadeem, Reza Kiarash, Peter Brent Sampson, Sam Wei, Radek Laufer, Irina Beletskaya, Henry W. Pauls, Jacqueline M. Mason, Sze-Wan Li, Xunyi Luo, Miklos Feher, Yong Liu, Bryan T. Forrest, Genie Leung, James Guohua Pan, Don Awrey, Yunhui Lang, Tak W. Mak, Ping Huang |
|---|---|
| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:LB-215 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2011-lb-215 |
| Popis: | Polo-like kinase 4 or PLK4 is a member of a conserved family of serine/threonine protein kinases that regulate multiple cellular processes, such as cell division and checkpoint regulation of mitosis. These kinases are often deregulated in cancer. PLK4 is the most structurally divergent PLK, localizes to centrosomes and is a critical regulator of centriole duplication. Over-expression of PLK4 leads to centrosome amplification and results in chromosome instability (CIN), a common characteristic observed in many types of cancers. We found that PLK4 is upregulated in breast cancer, specifically in the basal-like subtype. PLK4 expression is induced by hypoxia and suppressed by p53 in cancer cells. Consistent with this observation, PLK4 expression in cancer cells is upregulated when they are implanted and grown as xenografts in vivo. Furthermore, RNAi-mediated depletion of PLK4 inhibits the growth of cancer cells, but not normal cells (HMEC), in vitro, and tumor growth in vivo. Interestingly, siRNA knockdown of PLK4 sensitizes cancer cells to hypoxia. These findings suggest that targeting PLK4 may be a good therapeutic strategy in treating certain cancers. To this end, we initiated a discovery program that resulted in the identification of potent PLK4 inhibitors. These novel inhibitors are potent anti-prolifeartives, cause loss of mitotic checkpoint followed by apoptotic cell death, and suppress tumor growth in xenograft models. Mechanistically, inhibition of PLK4 suppresses phosphorylation of PLK4 and Histone H3, leads to failure of centrosome clustering and formation of multipolar spindles. Interestingly, breast cancer cell response to PLK4 inhibition appears to differ among subtypes of breast cancer cells and to be influenced by receptor and mutation status, such as ER and PTEN. Since multipolar division in cancer cells is not viable, due to massive missegregation of chromosomes, inhibition of PLK4 and formation of multipolar division followed by cell death may be a unique strategy for killing cancer cells. Implications of these findings in treating cancer will also be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2011-LB-215 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|