A35
PDF (Prostate Derived Factor) is a novel modulator of drug response in colorectal cancer cells
Irina Proutski, Leanne Stevenson, Andrea McCulla, Wendy Allen, Daniel Longley, Patrick Johnston
CCRCB Quenns University, Belfast, Northern Ireland, UK
Prostate derived factor, a member of TGFβ superfamily, is involved in tumour development and progression. Initial DNA microarray experiments were carried out in HCT116 sensitive and resistant colorectal cancer (CRC) cell lines and aimed to identify genes that are involved in resistance to chemotherapy in CRC. The results from the microarray studies demonstrated that PDF is highly inducible after treatment with Oxaliplatin, 5-Fluorouracil and SN38 (active component of Irinotecan). Further studies in p53wt HCT116 and LoVo cells demonstrated increased PDF expression at both mRNA and protein levels. No induction of PDF expression was observed in HCT116 p53 null cells and other p53 mutant cell lines (H630, HT29).
PDF silencing prior to drug treatment in HCT116 p53wild type cells led to increased cell death. A similar effect was observed in HCT116 drug resistant cell lines, suggesting that PDF knock-out sensitizes drug-resistant cells to chemotherapy. No increase in apoptosis was detected in LoVo cells, which are deficient in the enzyme that processes the PDF precursor to its mature secreted form, after PDF silencing combined with chemotreatment. Overexpression of PDF in the HCT116 p53 wild type cell line as well as treatment of LoVo cells with recombinant PDF, on the other hand, was shown to rescue cells from apoptosis. Thus, PDF appears to be an important mediator in the development of drug resistance and may represent a novel druggable target.
