Sensitization of breast cancer cells to taxol by inhibition of taxol resistance gene 1

Bai,Zhigang; Zhang,Zhongtao; Qu,Xiang; Han,Wei; Ma,Xuemei

doi:10.3892/ol.2011.416

Sensitization of breast cancer cells to taxol by inhibition of taxol resistance gene 1

Authors:
- Zhigang Bai
- Zhongtao Zhang
- Xiang Qu
- Wei Han
- Xuemei Ma
View Affiliations

Affiliations: Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
Published online on: September 9, 2011 https://doi.org/10.3892/ol.2011.416
Pages: 135-140

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The purpose of this study was to determine the role of taxol resistance gene 1 (TXR1) in a taxol-resistant breast cancer cell line. Expression levels of TXR1 and thrombospondin-1 (TSP1) were detected by RT-PCR and Western blot analysis. In MCF-7 cells transfected with TXR1 plasmids, the expression of a number of drug resistance genes was monitored, as well as cell proliferation. MCF-7 cells were also transiently transfected with a chemically synthesized small interfering RNA (siRNA) targeting TXR1. Taxol concentrations varying from 0.6 to 6 µg/ml were shown to inhibit the proliferation of MCF-7 cells in a time- and dose-dependent manner by arresting cells in the G2/M phase. Additionally, 0.06 µg/ml taxol was used to establish a taxol-resistant MCF-7 cell line, MCF-7/T. When TXR1 was exogenously expressed, a taxol-resistant phenotype was further induced and the expression levels of BCRP, GSTP1 and MVP increased. Transient transfection of TXR1-targeting siRNAs was shown to restore the chemosensitivity of MCF-7 cells. These results suggest that an increased expression of TXR1 is a novel mechanism for reversing the taxol resistance of breast cancer cells.

View Figures

View References

1	Marsh S and McLeod HL: Pharmacogenetics and oncology treatment for breast cancer. Expert Opin Pharmacother. 8:119–127. 2007. View Article : Google Scholar : PubMed/NCBI
2	Moore A: Breast-cancer therapy-looking back to the future. N Engl J Med. 357:1547–1549. 2007. View Article : Google Scholar
3	Horwitz SB: Mechanism of action of taxol. Trends Pharmacol Sci. 13:134–136. 1992. View Article : Google Scholar
4	Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC and Davidson NE: Weekly paclitaxel in the adjuvant treatment of breast cancer. New Engl J Med. 358:1663–1671. 2008. View Article : Google Scholar : PubMed/NCBI
5	Broxterman HJ, Gotink KJ and Verheul HM: Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. Drug Resist Updat. 12:114–126. 2009. View Article : Google Scholar : PubMed/NCBI
6	Sangrajrang S and Fellous A: Taxol resistance. Chemotherapy. 46:327–334. 2000. View Article : Google Scholar
7	Martello LA, Verdier-Pinard P, Shen HJ, He L, Torres K, Orr GA and Horwitz SB: Elevated levels of microtubule destabilizing factors in a taxol-resistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res. 63:1207–1213. 2003.PubMed/NCBI
8	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
9	Ferguson T, Wilcken N, Vagg R, Ghersi D and Nowak AK: Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst Rev. 17:CD0044212007.PubMed/NCBI
10	Kutuk O and Letai A: Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737. Cancer Res. 68:7985–7994. 2008. View Article : Google Scholar : PubMed/NCBI
11	Hudis C and Dang C: The taxane limbo: how low can we go? J Natl Cancer Inst. 100:761–763. 2008. View Article : Google Scholar : PubMed/NCBI
12	Lih CJ, Wei W and Cohen SN: Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes. Genes Dev. 20:2082–2095. 2006. View Article : Google Scholar : PubMed/NCBI
13	Nor JE, Mitra RS, Sutorik MM, Mooney DJ, Castle VP and Polverini PJ: Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res. 37:209–218. 2000. View Article : Google Scholar : PubMed/NCBI
14	Papadaki C, Mavroudis D, Trypaki M, Koutsopoulos A, Stathopoulos E, Hatzidaki D, Tsakalaki E, Georgoulias V and Souglakos J: Tumoral Expression of TXR1 and TSP1 predicts overall survival of patients with lung adenocarcinoma treated with first-line docetaxel-gemcitabine regimen. Clin Cancer Res. 15:3827–3833. 2009. View Article : Google Scholar : PubMed/NCBI
15	Greenberger LM, Lothstein L, Williams SS and Horwitz SB: Distinct P-glycoprotein precursors are overproduced in independently isolated drug-resistant cell lines. Proc Natl Acad Sci USA. 85:3762–3766. 1988. View Article : Google Scholar : PubMed/NCBI
16	Jordan MA and Wilson L: Microtubules as a target for anticancer drugs. Nat Rev Cancer. 4:253–265. 2004. View Article : Google Scholar : PubMed/NCBI
17	Van Amerongen R and Berns A: TXR1-mediated thrombospondin repression: a novel mechanism of resistance to taxanes? Genes Dev. 20:1975–1981. 2006.PubMed/NCBI
18	Orr GA, Verdier-Pinard P, McDaid H and Horwitz SB: Mechanisms of taxol resistance related to microtubules. Oncogene. 22:7280–7295. 2003. View Article : Google Scholar : PubMed/NCBI
19	Ark-Otte J, Samelis G, Rubio G, Lopez Saez JB, Pinedo HM and Giaccone G: Effects of tubulin-inhibiting agents in human lung and breast cancer cell lines with different multidrug resistance phenotypes. Oncol Rep. 5:249–255. 1998.PubMed/NCBI
20	McGrogan BT, Gilmartin B, Carney DN and McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 1785:96–132. 2008.PubMed/NCBI
21	Lavie Y, Cao H, Volner A, Lucci A, Han TY, Geffen V, Giuliano AE and Cabot MC: Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem. 272:1682–1687. 1997. View Article : Google Scholar
22	Longley D and Johnston P: Molecular mechanisms of drug resistance. J Pathol. 205:275–292. 2005. View Article : Google Scholar