Skip to main content
Top
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Short communication

Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo

Authors: Didier Roulin, Yannick Cerantola, Anne Dormond-Meuwly, Nicolas Demartines, Olivier Dormond

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

The mammalian target of rapamycin (mTOR), which exists in two functionally distinct complexes, mTORC1 and mTORC2 plays an important role in tumor growth. Whereas the role of mTORC1 has been well characterized in this process, little is known about the functions of mTORC2 in cancer progression. In this study, we explored the specific role of mTORC2 in colon cancer using a short hairpin RNA expression system to silence the mTORC2-associated protein rictor. We found that downregulation of rictor in HT29 and LS174T colon cancer cells significantly reduced cell proliferation. Knockdown of rictor also resulted in a G1 arrest as observed by cell cycle analysis. We further observed that LS174T cells deficient for rictor failed to form tumors in a nude mice xenograft model. Taken together, these results show that the inhibition of mTORC2 reduces colon cancer cell proliferation in vitro and tumor xenograft formation in vivo. They also suggest that specifically targeting mTORC2 may provide a novel treatment strategy for colorectal cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell. 2006, 124: 471-484. 10.1016/j.cell.2006.01.016CrossRefPubMed Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell. 2006, 124: 471-484. 10.1016/j.cell.2006.01.016CrossRefPubMed
2.
go back to reference Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 2004, 18: 1926-1945. 10.1101/gad.1212704CrossRefPubMed Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 2004, 18: 1926-1945. 10.1101/gad.1212704CrossRefPubMed
3.
go back to reference Guertin DA, Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 2007, 12: 9-22. 10.1016/j.ccr.2007.05.008CrossRefPubMed Guertin DA, Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 2007, 12: 9-22. 10.1016/j.ccr.2007.05.008CrossRefPubMed
4.
go back to reference Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006, 22: 159-168. 10.1016/j.molcel.2006.03.029CrossRefPubMed Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006, 22: 159-168. 10.1016/j.molcel.2006.03.029CrossRefPubMed
5.
go back to reference Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005, 307: 1098-1101. 10.1126/science.1106148CrossRefPubMed Sarbassov DD, Guertin DA, Ali SM, Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005, 307: 1098-1101. 10.1126/science.1106148CrossRefPubMed
6.
go back to reference Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN: Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004, 6: 1122-1128. 10.1038/ncb1183CrossRefPubMed Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN: Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004, 6: 1122-1128. 10.1038/ncb1183CrossRefPubMed
7.
go back to reference Faivre S, Kroemer G, Raymond E: Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006, 5: 671-688. 10.1038/nrd2062CrossRefPubMed Faivre S, Kroemer G, Raymond E: Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006, 5: 671-688. 10.1038/nrd2062CrossRefPubMed
8.
go back to reference Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J: mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 2007, 67: 11712-11720. 10.1158/0008-5472.CAN-07-2223CrossRefPubMed Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J: mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 2007, 67: 11712-11720. 10.1158/0008-5472.CAN-07-2223CrossRefPubMed
9.
go back to reference Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM: mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell. 2009, 15: 148-159. 10.1016/j.ccr.2008.12.017PubMedCentralCrossRefPubMed Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM: mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell. 2009, 15: 148-159. 10.1016/j.ccr.2008.12.017PubMedCentralCrossRefPubMed
10.
go back to reference Rychahou PG, Kang J, Gulhati P, Doan HQ, Chen LA, Xiao SY, Chung DH, Evers BM: Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci USA. 2008, 105: 20315-20320. 10.1073/pnas.0810715105PubMedCentralCrossRefPubMed Rychahou PG, Kang J, Gulhati P, Doan HQ, Chen LA, Xiao SY, Chung DH, Evers BM: Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci USA. 2008, 105: 20315-20320. 10.1073/pnas.0810715105PubMedCentralCrossRefPubMed
11.
go back to reference Zhang YJ, Dai Q, Sun DF, Xiong H, Tian XQ, Gao FH, Xu MH, Chen GQ, Han ZG, Fang JY: mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol. 2009, 16: 2617-2628. 10.1245/s10434-009-0555-9CrossRefPubMed Zhang YJ, Dai Q, Sun DF, Xiong H, Tian XQ, Gao FH, Xu MH, Chen GQ, Han ZG, Fang JY: mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol. 2009, 16: 2617-2628. 10.1245/s10434-009-0555-9CrossRefPubMed
12.
go back to reference Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM: Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci USA. 2008, 105: 13544-13549. 10.1073/pnas.0800041105PubMedCentralCrossRefPubMed Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM: Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci USA. 2008, 105: 13544-13549. 10.1073/pnas.0800041105PubMedCentralCrossRefPubMed
13.
go back to reference Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009, 284: 8023-8032. 10.1074/jbc.M900301200PubMedCentralCrossRefPubMed Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009, 284: 8023-8032. 10.1074/jbc.M900301200PubMedCentralCrossRefPubMed
14.
go back to reference Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM: Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009, 7: e38- 10.1371/journal.pbio.1000038CrossRefPubMed Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM: Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009, 7: e38- 10.1371/journal.pbio.1000038CrossRefPubMed
15.
go back to reference Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ: Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 2009, 69: 6232-6240. 10.1158/0008-5472.CAN-09-0299CrossRefPubMed Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ: Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res. 2009, 69: 6232-6240. 10.1158/0008-5472.CAN-09-0299CrossRefPubMed
Metadata
Title
Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo
Authors
Didier Roulin
Yannick Cerantola
Anne Dormond-Meuwly
Nicolas Demartines
Olivier Dormond
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-57

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine