Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer

David Luyimbazi, Argun Akcakanat, Priscilla F. McAuliffe, Li Zhang, Gopal Singh, Ana Maria Gonzalez-Angulo, Huiqin Chen, Kim Anh Do, Yuhuan Zheng, Mien Chie Hung, Gordon Mills, Funda Meric-Bernstam

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Mammalian target of rapamycin (mTOR) signaling is a central regulator of protein translation, cell growth, and metabolism. Alterations of the mTOR signaling pathway are common in cancer, making mTOR a promising therapeutic target. In clinical trials, rapamycin analogs have shown modest response rates for most cancer types, including breast cancer. Therefore, there is an urgent need to better understand the mechanism of action of rapamycin to improve patient selection and to monitor pathway inhibition. To identify novel pharmacodynamic markers of rapamycin activity, we carried out transcriptional profiling of total and polysome-associated RNA in three breast cancer cell lines representing different subtypes. In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, whereas rapamycin, LY294002, and BEZ235 decreased SCD1 protein expression. Rapamycin decreased total SCD1 RNA expression without inducing a significant decline in its relative polysomal recruitment (polysome/total ratio). Rapamycin did not alter SCD1 mRNA stability. Instead, rapamycin inhibited SCD1 promoter activity and decreased expression of mature transcription factor sterol regulatory element binding protein 1 (SREBP1). Eukaryotic initiation factor 4E (eIF4E) small interfering RNA (siRNA) decreased both SCD1 and SREBP1 expression, suggesting that SCD1 may be regulated through the mTOR/eIF4E-binding protein 1 axis. Furthermore, SCD1 siRNA knockdown inhibited breast cancer cell growth, whereas overexpression increased growth. Taken together these findings show that rapamycin decreases SCD1 expression, establishing an important link between cell signaling and cancer cell fatty acid synthesis and growth.

Original languageEnglish (US)
Pages (from-to)2770-2784
Number of pages15
JournalMolecular Cancer Therapeutics
Volume9
Issue number10
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

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Stearoyl-CoA Desaturase
Sirolimus
Breast Neoplasms
Polyribosomes
Eukaryotic Initiation Factor-4E
Sterol Regulatory Element Binding Protein 1
Growth
Small Interfering RNA
RNA
Cell Line
Monounsaturated Fatty Acids
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
RNA Stability
Protein Biosynthesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Luyimbazi, D., Akcakanat, A., McAuliffe, P. F., Zhang, L., Singh, G., Gonzalez-Angulo, A. M., ... Meric-Bernstam, F. (2010). Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Molecular Cancer Therapeutics, 9(10), 2770-2784. https://doi.org/10.1158/1535-7163.MCT-09-0980

Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. / Luyimbazi, David; Akcakanat, Argun; McAuliffe, Priscilla F.; Zhang, Li; Singh, Gopal; Gonzalez-Angulo, Ana Maria; Chen, Huiqin; Do, Kim Anh; Zheng, Yuhuan; Hung, Mien Chie; Mills, Gordon; Meric-Bernstam, Funda.

In: Molecular Cancer Therapeutics, Vol. 9, No. 10, 01.10.2010, p. 2770-2784.

Research output: Contribution to journalArticle

Luyimbazi, D, Akcakanat, A, McAuliffe, PF, Zhang, L, Singh, G, Gonzalez-Angulo, AM, Chen, H, Do, KA, Zheng, Y, Hung, MC, Mills, G & Meric-Bernstam, F 2010, 'Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer', Molecular Cancer Therapeutics, vol. 9, no. 10, pp. 2770-2784. https://doi.org/10.1158/1535-7163.MCT-09-0980
Luyimbazi D, Akcakanat A, McAuliffe PF, Zhang L, Singh G, Gonzalez-Angulo AM et al. Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Molecular Cancer Therapeutics. 2010 Oct 1;9(10):2770-2784. https://doi.org/10.1158/1535-7163.MCT-09-0980
Luyimbazi, David ; Akcakanat, Argun ; McAuliffe, Priscilla F. ; Zhang, Li ; Singh, Gopal ; Gonzalez-Angulo, Ana Maria ; Chen, Huiqin ; Do, Kim Anh ; Zheng, Yuhuan ; Hung, Mien Chie ; Mills, Gordon ; Meric-Bernstam, Funda. / Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 10. pp. 2770-2784.
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