Journal
MOLECULAR CANCER THERAPEUTICS
Volume 8, Issue 9, Pages 2566-2574Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-09-0158
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Funding
- Cancer Research UK
- Action Cancer, Research and Development Office, Northern Ireland
- Department for Employment and Learning, Northern Ireland
- Public Health Agency [RRG/3261/05] Funding Source: researchfish
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We investigated the role of the divergent transforming growth factor-beta superfamily member, prostate-derived factor (PDF), in regulating response to chemotherapies used in the treatment of colorectal cancer. A clear p53-dependent expression pattern of PDF was shown in a panel of colorectal cancer cell lines following acute exposure to oxaliplatin, 5-fluorouracil, and SN38. PDF gene silencing before chemotherapy treatment significantly sensitized cells expressing wild-type p53, but not p53-null or p53-mutant cells, to drug-induced apoptosis. Similarly, knockdown of PDF expression sensitized HCT116 drug-resistant daughter cell lines to their respective chemotherapies. Inducible PDF expression and treatment with recombinant PDF both significantly attenuated drug-induced apoptosis. Further analysis revealed that PDF activated the Akt but not the extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, cotreatment with the phosphatidylinositol 3-kinase inhibitor wortmannin abrogated PDF-mediated resistance to chemotherapy-induced apoptosis. Together, these data suggest that PDF may be a novel inhibitor of drug-induced cell death in colorectal cancer cells and that the mature secreted form of the protein activates the phosphatidylinositol 3-kinase/Akt pathway as an acute mechanism of chemoresistance. [Mol Cancer Ther 2009;8(9):2566-74]
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