Oxaliplatin Induces Different Cellular and Molecular Chemoresistance Patterns in Colorectal Cancer Cell Lines of Identical Origins

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2013 Jul 20

PMID 23865481

Citations 17

Authors

Piroska Virag

Eva Fischer-Fodor

Maria Perde-Schrepler

Ioana Brie

Corina Tatomir

Loredana Balacescu

Ioana Berindan-Neagoe

Bogdan Victor

Ovidiu Balacescu

Affiliations

Soon will be listed here.

Abstract

Background: Cancer cells frequently adopt cellular and molecular alterations and acquire resistance to cytostatic drugs. Chemotherapy with oxaliplatin is among the leading treatments for colorectal cancer with a response rate of 50%, inducing intrastrand cross-links on the DNA. Despite of this drug's efficiency, resistance develops in nearly all metastatic patients. Chemoresistance being of crucial importance for the drug's clinical efficiency this study aimed to contribute to the identification and description of some cellular and molecular alterations induced by prolonged oxaliplatin therapy. Resistance to oxaliplatin was induced in Colo320 (Colo320R) and HT-29 (HT-29R) colorectal adenocarcinoma cell lines by exposing the cells to increasing concentrations of the drug. Alterations in morphology, cytotoxicity, DNA cross-links formation and gene expression profiles were assessed in the parental and resistant variants with microscopy, MTT, alkaline comet and pangenomic microarray assays, respectively.

Results: Morphology analysis revealed epithelial-to-mesenchymal transition in the resistant vs parental cells suggesting alterations of the cells' adhesion complexes, through which they acquire increased invasiveness and adherence. Cytotoxicity measurements demonstrated resistance to oxaliplatin in both cell lines; Colo320 being more sensitive than HT-29 to this drug (P < 0.001). The treatment with oxaliplatin caused major DNA cross-links in both parental cell lines; in Colo320R small amounts of DNA cross-links were still detectable, while in HT-29R not. We identified 441 differentially expressed genes in Colo320R and 613 in HT-29R as compared to their parental counterparts (at least 1.5 -fold up- or down- regulation, p < 0.05). More disrupted functions and pathways were detected in HT-29R cell line than in Colo320R, involving genes responsible for apoptosis inhibition, cellular proliferation and epithelial-to-mesenchymal transition. Several upstream regulators were detected as activated in HT-29R cell line, but not in Colo320R.

Conclusions: Our findings revealed a more resistant phenotype in HT-29R as compared to Colo320R and different cellular and molecular chemoresistance patterns induced by prolonged treatment with oxaliplatin in cell lines with identical origins (colorectal adenocarcinomas).

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References

Duque J, Fresno M, Iniguez M . Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 2005; 280(10):8686-93. DOI: 10.1074/jbc.M413076200. View

Misset J, Bleiberg H, Sutherland W, Bekradda M, Cvitkovic E . Oxaliplatin clinical activity: a review. Crit Rev Oncol Hematol. 2000; 35(2):75-93. DOI: 10.1016/s1040-8428(00)00070-6. View

Kumar A, Xu J, Brady S, Gao H, Yu D, Reuben J . Tissue transglutaminase promotes drug resistance and invasion by inducing mesenchymal transition in mammary epithelial cells. PLoS One. 2010; 5(10):e13390. PMC: 2953521. DOI: 10.1371/journal.pone.0013390. View

Desoize B, Madoulet C . Particular aspects of platinum compounds used at present in cancer treatment. Crit Rev Oncol Hematol. 2002; 42(3):317-25. DOI: 10.1016/s1040-8428(01)00219-0. View

Hovhannisyan G, Haroutunyan T, Arutyunyan R . Evaluation of cisplatin-DNA crosslinks formation with UV-C application by the alkaline Comet-assay. Exp Oncol. 2004; 26(3):240-2. View

Matsumiya T, Prescott S, Stafforini D . IFN-epsilon mediates TNF-alpha-induced STAT1 phosphorylation and induction of retinoic acid-inducible gene-I in human cervical cancer cells. J Immunol. 2007; 179(7):4542-9. DOI: 10.4049/jimmunol.179.7.4542. View

Miyoshi N, Ishii H, Mimori K, Tanaka F, Hitora T, Tei M . TGM2 is a novel marker for prognosis and therapeutic target in colorectal cancer. Ann Surg Oncol. 2009; 17(4):967-72. DOI: 10.1245/s10434-009-0865-y. View

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

Yang A, Fan F, Camp E, Van Buren G, Liu W, Somcio R . Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006; 12(14 Pt 1):4147-53. DOI: 10.1158/1078-0432.CCR-06-0038. View

10.

McCord A, Jamal M, Williams E, Camphausen K, Tofilon P . CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res. 2009; 15(16):5145-53. PMC: 6290462. DOI: 10.1158/1078-0432.CCR-09-0263. View

11.

Laurent A, Nicco C, Chereau C, Goulvestre C, Alexandre J, Alves A . Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res. 2005; 65(3):948-56. View

12.

Sullivan B, Cherry J, Sakamoto H, Henkes L, Townson D, Rueda B . Cytokeratin 18 expression inhibits cytokine-induced death of cervical cancer cells. Int J Gynecol Cancer. 2010; 20(9):1474-81. DOI: 10.1111/IGC.0b013e3181fc3a03. View

13.

Huang L, Li M, Wang L, Li B, Chen G, He L . Prognostic value of Wnt inhibitory factor-1 expression in hepatocellular carcinoma that is independent of gene methylation. Tumour Biol. 2010; 32(1):233-40. DOI: 10.1007/s13277-010-0117-6. View

14.

Virag P, Brie I, Fischer-Fodor E, Perde-Schrepler M, Tatomir C, Balacescu O . Assessment of cytotoxicity, apoptosis and DNA damages in Colo320 colorectal cancer cells selected for oxaliplatin resistance. Cell Biochem Funct. 2011; 29(5):351-5. DOI: 10.1002/cbf.1754. View

15.

Unger F, Klasen H, Tchartchian G, De Wilde R, Witte I . DNA damage induced by cis- and carboplatin as indicator for in vitro sensitivity of ovarian carcinoma cells. BMC Cancer. 2009; 9:359. PMC: 2768745. DOI: 10.1186/1471-2407-9-359. View

16.

Yang L, Cao Z, Yan H, Wood W . Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res. 2003; 63(20):6815-24. View

17.

Gerlach K, Daniel C, Lehr H, Nikolaev A, Gerlach T, Atreya R . Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis. Cancer Res. 2012; 72(17):4340-50. DOI: 10.1158/0008-5472.CAN-11-4155. View

18.

Andreu P, Colnot S, Godard C, Laurent-Puig P, Lamarque D, Kahn A . Identification of the IFITM family as a new molecular marker in human colorectal tumors. Cancer Res. 2006; 66(4):1949-55. DOI: 10.1158/0008-5472.CAN-05-2731. View

19.

Cavallaro U, Christofori G . Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004; 4(2):118-32. DOI: 10.1038/nrc1276. View

20.

Shao M, Cao L, Shen C, Satpathy M, Chelladurai B, Bigsby R . Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. Cancer Res. 2009; 69(24):9192-201. DOI: 10.1158/0008-5472.CAN-09-1257. View