Lentiviral shRNA screen of human kinases identifies PLK1 as a potential therapeutic target for osteosarcoma

Zhenfeng Duan, Diana Ji, Edward J. Weinstein, Xianzhe Liu, Michiro Susa, Edwin Choy, Cao Yang, Henry Mankin, Francis J. Hornicek

研究成果: Article査読

48 被引用数 (Scopus)

抄録

We describe an optimized systematic screen of known kinases using osteosarcoma cell lines (KHOS and U-2OS) and a lentiviral-based short hairpin RNA (shRNA) human kinase library. CellTiter 96®AQueous One Solution Cell Proliferation Assay was used to measure cell growth and survival. We identified several kinases, including human polo-like kinase (PLK1), which inhibit cell growth and induce apoptosis in osteosarcoma cells when knocked down. cDNA rescue and synthetic siRNA assays confirm that the observed phenotypic changes result from the loss of PLK1 gene expression.Furthermore, a small molecule inhibitor to PLK1 inhibited osteosarcoma cell growth and induced apoptosis. Western blot analysis confirmed that PLK1 is highly expressed and activated in several osteosarcoma cell lines as well as in resected tumor samples. Immunohistochemistry analysis showed that patients with high PLK1 tumor expression levels correlated with significantly shorter survival than patients with lower levels of tumor PLK1 expression. These results demonstrate the capability and feasibility of a high-throughput screen with a large collection of lentiviral kinases and its effectiveness in identifying potential drug targets. The development of more potent inhibitors that target PLK1 may open doors to a new range of anti-cancer strategies in osteosarcoma.

本文言語English
ページ(範囲)220-229
ページ数10
ジャーナルCancer Letters
293
2
DOI
出版ステータスPublished - 2010 7

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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