Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer

Celine J. Guigon, Laura Fozzatti, Changxue Lu, Mark C. Willingham, Sheue Yann Cheng

Research output: Contribution to journalArticle

Abstract

Selective drugs targeting dysregulated oncogenic pathways are promising cancer therapies. Because the mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in human follicular thyroid cancer (FTC), we hypothesized that its inhibition could block cancer development and progression. We, therefore, analyzed the effect of a treatment with a specific mTORC1 inhibitor (RAD001) in a faithful mouse model of FTC with constitutive mTORC1 activation (TRβPV/PVPten+/- mice). The treatment did not prevent capsular and vascular invasion of the thyroid and the occurrence of lung metastasis. However, it substantially decelerated thyroid tumor growth, thereby prolonging TRβPV/PVPten+/- mouse life span. RAD001 efficiently inhibited mTORC1 activity, as shown by the reduced phosphorylation of its downstream targets involved in the activity of the translation machinery, such as ribosomal S6 kinase (p70S6K), eukaryotic translation initiation factor 4E binding protein (4E-BP1) and the eukaryotic translation initiation factors eIF-4B and eIF-4G. Whereas mTORC1 signaling inhibition did not alter cell apoptosis, it induced a significant decrease in cell proliferation that was associated with the reduced abundance and altered activity of key regulators of cell cycle progression. Altogether, our data indicate that mTORC1 signaling plays a major role in the integration of the mitogenic signal in FTC. Therefore, our preclinical study with a relevant mouse model of FTC demonstrates for the first time that RAD001 efficaciously stabilizes cancer growth although it does not prevent its fatal outcome. In conclusion, our work underscores that in the treatment of FTC patients, RAD001 can only be used in combination with drugs and therapies inducing tumor shrinkage and blocking metastasis.

Original languageEnglish (US)
Pages (from-to)1284-1291
Number of pages8
JournalCarcinogenesis
Volume31
Issue number7
DOIs
StatePublished - Mar 18 2010
Externally publishedYes

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Thyroid Neoplasms
Growth
Eukaryotic Initiation Factors
Neoplasms
Thyroid Gland
Eukaryotic Initiation Factor-4E
Ribosomal Protein S6 Kinases
Neoplasm Metastasis
70-kDa Ribosomal Protein S6 Kinases
Fatal Outcome
Therapeutics
Drug Delivery Systems
Combination Drug Therapy
Blood Vessels
mechanistic target of rapamycin complex 1
Cell Cycle
Carrier Proteins
Phosphorylation
Cell Proliferation
Follicular Thyroid cancer

ASJC Scopus subject areas

  • Cancer Research

Cite this

Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer. / Guigon, Celine J.; Fozzatti, Laura; Lu, Changxue; Willingham, Mark C.; Cheng, Sheue Yann.

In: Carcinogenesis, Vol. 31, No. 7, 18.03.2010, p. 1284-1291.

Research output: Contribution to journalArticle

Guigon, Celine J. ; Fozzatti, Laura ; Lu, Changxue ; Willingham, Mark C. ; Cheng, Sheue Yann. / Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer. In: Carcinogenesis. 2010 ; Vol. 31, No. 7. pp. 1284-1291.
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