Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells

Oncogene volume 20, pages 4995–5004 (2001)Cite this article

Abstract

Inherent or acquired drug resistance is one of the major problems in chemotherapy. The mechanisms by which cancer cells survive and escape the cytotoxic effects of chemotherapeutic agents are essentially unknown. In the present study, we demonstrate that in the MDA-MB-231 and MDA-MB-435 breast cancer cells, ligation of β1 integrins by their extracellular matrix ligands inhibits significantly apoptosis induced by paclitaxel and vincristine, two microtubule-directed chemotherapeutic agents that are widely used in the therapy of breast cancer. We show that β1 integrin signaling inhibits drug-induced apoptosis by inhibiting the release of cytochrome c from the mitochondria in response to drug treatment. Further, integrin-mediated protection from drug-induced apoptosis and inhibition of cytochrome c release are dependent on the activation of the PI 3-kinase/Akt pathway. Our results identify β1 integrin signaling as an important survival pathway in drug-induced apoptosis in breast cancer cells and suggest that activation of this pathway may contribute to the generation of drug resistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

ECM:

extracellular matrix

GFP:

green fluorescent protein

PI 3-kinase:

phosphatidyl inositol 3′-kinase

References

  • Almeida EA, Ilic D, Han Q, Hauck CR, Jin F, Kawakatsu H, Schlaepfer DD, Damsky CH . 2000 J. Cell Biol. 149: 741–754

  • Aoudjit F, Vuori K . 2000 Blood 95: 2044–2051

  • Aoudjit F, Vuori K . 2001 J. Cell Biol. 152: 633–643

  • Blagosklonny MV, Giannakakou P, El-Deiry WS, Kingston DG, Higgs PI, Neckers L, Fojo T . 1997 Cancer Res. 57: 130–135

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC . 1998 Science 282: 1318–1321

  • Chadebech P, Brichese L, Baldin V, Vidal S, Valette A . 1999 Biochem. Biophys. Res. Commun. 262: 823–827

  • Coleman RE, Rubens RD . 1987 Br. J. Cancer 55: 61–66

  • Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . 1999 Blood 93: 1658–1667

  • Datta SR, Brunet A, Greenberg ME . 1999 Genes Dev. 13: 2905–2927

  • Fisher B, Osborne CK, Margolese RG, Bloomer WD . 1997 Cancer Medicine 4th edition. Holland JF, Bast RC, Morton DL, Frei E, Kufe DW and Weichselbaum RR. (eds) Williams & Wilkins: Baltimore, MD

    Google Scholar 

  • Fornier M, Munster P, Seidman AD . 1999 Oncology 13: 647–658

  • Frisch SM, Ruoslahti E . 1997 Curr. Opin. Cell Biol. 9: 701–706

  • Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY . 1996 J. Cell Biol. 134: 793–799

  • Giancotti FG, Ruoslahti E . 1999 Science 285: 1028–1032

  • Gilmore AP, Metcalfe AD, Romer LH, Streuli CH . 2000 J. Cell Biol. 149: 431–446

  • Gooch JL, Van Den Berg CL, Yee D . 1999 Breast Cancer Res. Treat. 56: 1–10

  • Green DR, Reed JC . 1998 Science 281: 1309–1312

  • Gross A, McDonnell JM, Korsmeyer SJ . 1999 Genes Dev. 13: 1899–1911

  • Haldar S, Basu A, Croce CM . 1997 Cancer Res. 57: 229–233

  • Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS . 2000 Oncogene 19: 4319–4327

  • Hungerford JE, Compton MT, Matter ML, Hoffstrom BG, Otey CA . 1996 J. Cell Biol. 135: 1383–1390

  • Ilic D, Almeida EA, Schlaepfer DD, Dazin P, Aizawa S, Damsky CH . 1998 J. Cell Biol. 143: 547–560

  • Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC . 1998 Proc. Natl. Acad. Sci. USA 95: 4997–5002

  • Kaufmann SH, Earnshaw WC . 2000 Exp. Cell Res. 256: 42–49

  • Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . 1997 EMBO J. 16: 2783–2793

  • Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD . 1997 Science 275: 1132–1136

  • Kottke TJ, Blajeski AL, Martins LM, Mesner Jr. PW, Davidson NE, Earnshaw WC, Armstrong DK, Kaufmann SH . 1999 J. Biol. Chem. 274: 15927–15936

  • Kumar N . 1981 J. Biol. Chem. 256: 10435–10441

  • Le Gall M, Chambard JC, Breittmayer JP, Grall D, Pouyssegur J, Van Obberghen-Schilling E . 2000 Mol. Biol. Cell 11: 1103–1112

  • Lebwohl DE, Canetta R . 1999 Ann. Oncol. 10: 139–146

  • Lee JW, Juliano RL . 2000 Mol. Biol. Cell 11: 1973–1987

  • Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . 1997 Cell 91: 479–489

  • Lichtner RB, Howlett AR, Lerch M, Xuan JA, Brink J, Langton-Webster B, Schneider MR . 1998 Exp. Cell Res. 240: 368–376

  • Lundstrom A, Holmbom J, Lindqvist C, Nordstrom T . 1998 Biochem. Biophys. Res. Commun. 250: 735–740

  • MacKeigan JP, Collins TS, Ting JP . 2000 J. Biol. Chem. 275: 38953–38956

  • Montgomery AM, Reisfeld RA, Cheresh DA . 1994 Proc. Natl. Acad. Sci. USA 91: 8856–8860

  • Nista A, Leonetti C, Bernardini G, Mattioni M, Santoni A . 1997 Int. J. Cancer 72: 133–141

  • O'Brien V, Frisch SM, Juliano RL . 1996 Exp. Cell Res. 224: 208–213

  • Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, Lin J . 2000 Anticancer Res. 20: 407–416

  • Petitclerc E, Stromblad S, von Schalscha TL, Mitjans F, Piulats J, Montgomery AM, Cheresh DA, Brooks PC . 1999 Cancer Res. 59: 2724–2730

  • Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE . 2000 J. Biol. Chem. 275: 10761–10766

  • Pusztai L, Siddik ZH, Mills GB, Bast RC . 1998 Acta Oncol. 37: 629–640

  • Rosen K, Rak J, Leung T, Dean NM, Kerbel RS, Filmus J . 2000 J. Cell Biol. 149: 447–456

  • Rytomaa M, Lehmann K, Downward J . 2000 Oncogene 19: 4461–4468

  • Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S . 1999 EMBO J. 18: 2040–2048

  • Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM . 1998 J. Cell Biol. 141: 1083–1093

  • Schlaepfer DD, Hauck CR, Sieg DJ . 1999 Prog. Biophys. Mol. Biol. 71: 435–478

  • Schwartz MA, Schaller MD, Ginsberg MH . 1995 Annu. Rev. Cell Dev. Biol. 11: 549–599

  • Seftor RE, Seftor EA, Sheng S, Pemberton PA, Sager R, Hendrix MJ . 1998 Cancer Res. 58: 5681–5685

  • Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnelly SC, Strieter R, Haslett C . 1999 Nat. Med. 5: 662–668

  • Shaw LM, Chao C, Wewer UM, Mercurio AM . 1996 Cancer Res. 56: 959–963

  • Shimizu S, Narita M, Tsujimoto Y . 1999 Nature 399: 483–487

  • Srivastava RK, Sasaki CY, Hardwick JM, Longo DL . 1999 J. Exp. Med. 190: 253–265

  • Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL . 1998 Mol. Cell. Biol. 18: 3509–3517

  • Uhm JH, Dooley NP, Kyritsis AP, Rao JS, Gladson CL . 1999 Clin. Cancer Res. 5: 1587–1594

  • van der Pluijm P, Vloedgraven H, Papapoulos S, Lowick C, Grzesik W, Kerr J, Robey PG . 1997 Lab. Invest. 77: 665–675

  • Vuori K, Ruoslahti E . 1995 J. Biol. Chem. 270: 22259–22262

  • Wang W, Passaniti A . 1999 J. Cell. Biochem. 73: 321–331

  • Wewer UM, Shaw LM, Albrechtsen R, Mercurio AM . 1997 Am. J. Pathol. 151: 1191–1198

  • Wong NC, Mueller BM, Barbas CF, Ruminski P, Quaranta V, Lin EC, Smith JW . 1998 Clin. Exp. Metast. 16: 50–61

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X . 1997 Science 275: 1129–1132

  • Yeung TK, Germond C, Chen X, Wang Z . 1999 Biochem. Biophys. Res. Commun. 263: 398–404

  • Zhang Z, Vuori K, Reed JC, Ruoslahti E . 1995 Proc. Natl. Acad. Sci. USA 92: 6161–6165

Download references

Acknowledgements

We thank Drs Jerrold Olefsky and Phil Tsichlis for providing some of the plasmids used in this study. We also thank Kathleen Becherer and Elise Larsen for their technical assistance. This work was supported by grants from NIH, California Breast Cancer Research Program and California Cancer Research Program (to K Vuori). K Vuori is a PEW scholar in biomedical sciences.

Author information

Authors and Affiliations

  1. Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, California, USA

    Fawzi Aoudjit & Kristiina Vuori

Authors
  1. Fawzi Aoudjit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristiina Vuori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristiina Vuori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aoudjit, F., Vuori, K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 20, 4995–5004 (2001). https://doi.org/10.1038/sj.onc.1204554

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204554

Keywords

This article is cited by

Search

Advanced search

Quick links