Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis.
The current chemotherapeutic modalities for advanced colorectal cancer are limited. DNA-platinating drugs such as cisplatin have poor efficacy against this malignancy. The aim of this study was to identify genes that render survival advantage after cisplatin treatment in metastatic colon cancer. Cell lines SW480 (primary colon cancer) and SW620 (metastatic lesion from the same patient) were obtained from ATCC. Apoptosis was measured by FACS analysis of cisplatin-treated (0.01-10 micro g/ml) and untreated cells. Simultaneous analysis of approximately 1200 cDNAs was performed by microarray technique on untreated and treated cells from lines. Microarray results were confirmed by RT-PCR. The SW620 cell line was more resistant to apoptosis induced by cisplatin. Western blot analysis revealed equal expression of pro-caspases 3, 8, and 9 in both cell lines. Microarray analysis identified 15 genes and 9 expressed sequence tags (ESTs) significantly altered both by cell type (metastatic vs. non-metastatic) and treatment vs. non-treatment. Several of these transcripts are well-characterized genes including MCT, GAD67, P19, GSTM3, Cyclin D1, ATM, and CO-029 that have been implicated in various malignancies. In the present study, we have identified a set of genes responsible for apoptosis resistance following treatment with cisplatin in the late stages of carcinogenesis. Targeting these genes may increase chemotherapy effectiveness in advanced colon cancer and reduce toxicity in normal tissue.
Huerta
Sergio
S
UCLA Center for Human Nutrition, and the David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-1742, USA. shuerta@pol.net
Harris
Diane M
DM
Jazirehi
Ali
A
Bonavida
Benjamin
B
Elashoff
David
D
Livingston
Edward H
EH
Heber
David
D
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D020224:Expressed Sequence Tags; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013382:Subtraction Technique
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D020169:Caspases; D002945:Cisplatin