APM2 is a novel mediator of cisplatin resistance in a variety of cancer cell types regardless of p53 or MMR status.
Cisplatin is one of the most widely used chemotherapeutics in the world today. Unfortunately, chemoresistance often develops hindering the effectiveness of the drug. Mismatch-repair (MMR) and p53 have previously been shown to be important determinants of cisplatin resistance and can contribute to cisplatin resistance clinically. Here, we have used cDNA microarray to identify several genes as up or downregulated in a previously described, cisplatin resistant, clone of the HCT116 cell line (HCT116-K). On follow-up, one gene, APM2, was found to promote cisplatin resistance when overexpressed in sensitive HCT116 clones. Furthermore, silencing APM2 in a panel of cell lines encompassing all combinations of p53 status and MMR proficiency (HCT116-K, HCT116, SW620, MCF7, PC-3 and OV2008) resulted in sensitization regardless of these 2 factors. In addition, silencing APM2 stably using shRNA also resulted in the sensitization of cells to cisplatin. More importantly, cisplatin inhibited the growth of APM2 silenced tumor xenografts (HCT116-K or OV2008 cells) significantly better than it inhibited the growth of xenografts carrying nontargeting control shRNAs. These findings represent a novel strategy that could be exploited to overcome cisplatin resistance in patients regardless of p53 status or ability to perform MMR.
Scott
Bradley J
BJ
Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada. brscott@ohri.ca
Qutob
Sami
S
Liu
Qing Y
QY
Ng
Cheng E
CE
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D053843:DNA Mismatch Repair / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
C499918:ADIPOQ protein, human; D052242:Adiponectin; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D045643:DNA Repair Enzymes; D002945:Cisplatin