التفاصيل البيبلوغرافية
| العنوان: |
PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas. |
| المؤلفون: |
Klein, Christian H., Truxius, Dina C., Vogel, Holger A., Harizanova, Jana, Murarka, Sandip, Martín‐Gago, Pablo, Bastiaens, Philippe I.H. |
| المصدر: |
International Journal of Cancer; Feb2019, Vol. 144 Issue 4, p767-776, 10p |
| مستخلص: |
Ras proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl‐binding protein PDEδ. Recently, we have reported the specific anti‐proliferative effects of PDEδ inhibition in KRas‐dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC. What's new? Oncogenic KRas mutations are present in about 45% of colorectal cancers (CRCs), where they are associated with poor prognosis. While KRas is an appealing therapeutic target, it has repeatedly eluded small‐molecule inhibitors. Here, the authors chose instead to target PDEδ, a prenyl‐binding protein that regulates the plasma membrane localization of KRas. In experiments in human colorectal cancer cells, PDEδ inhibition limited proliferation and survival in cells harboring KRas mutations, with no effect on wild‐type KRas cells, providing a new therapeutiv opportunity for CRC harbouring oncogenic KRas. In addition, PDEδ protein expression was correlated with oncogenic KRas activity within the CRC cell panel, suggesting that PDEδ protein‐level determination may be of prognostic relevance for CRC patients. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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