Prostate-derived factor--a novel inhibitor of drug-induced cell death in colon cancer cells.
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.
Proutski
Irina
I
Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
Stevenson
Leanne
L
Allen
Wendy L
WL
McCulla
Andrea
A
Boyer
John
J
McLean
Estelle G
EG
Longley
Daniel B
DB
Johnston
Patrick G
PG
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003470:Culture Media; D020868:Gene Silencing; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D003470:Culture Media; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53