Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells.
The interrelationship between platinum resistance and clinical response is not well established. The purpose of this study is to evaluate the expression of 14 genes involved in platinum resistance in a colon cancer cell line (HT29) and its oxaliplatin (OXA)-resistant sublines. Resistant cells exhibited lower expression of many of these genes suggesting that several pathways may be implicated in OXA resistance. Particularly, OXA resistance is accompanied by defects in drug uptake (downregulation of the hCTR1 transporter) and enhanced DNA repair (upregulation of the XPD gene). Our data also confirmed that copper transporters and chaperones are involved in OXA resistance in colorectal cancer cells as evidenced by the overexpression of ATP7A and CCS in response to OXA exposure. Moreover, increased CCS expression suggests a role for SOD1 in OXA detoxification. Whereas exposure to OXA in HT29 induced significant changes in expression of many of the genes analyzed, only ATP7A, XPD and SRPK1 gene expression was increased in OXA-treated HTOXAR3 resistant cells. To our knowledge, this is the first report of implicating SRPK1 in OXA resistance. This study provides the basis for further evaluation of these putative markers of OXA response and resistance in colorectal cancer patients who are candidates for treatment with OXA.
Plasencia
C
C
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, 90033, USA.
Martínez-Balibrea
E
E
Martinez-Cardús
A
A
Quinn
D I
DI
Abad
A
A
Neamati
N
N
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D019327:Copper Sulfate / Q000494:pharmacology; D000073840:Copper-Transporting ATPases; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D000251:Adenosine Triphosphatases; D045643:DNA Repair Enzymes; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D019327:Copper Sulfate; D002945:Cisplatin