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mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.
Oncotarget. 2016 May 03; 7(18):25224-40.O

Abstract

The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.

Links

Authors+Show Affiliations

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.

Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.

Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

MeSH

ATP Citrate (pro-S)-LyaseAcetyl Coenzyme ABreast NeoplasmsCell Line, TumorClass I Phosphatidylinositol 3-KinasesFemaleHumansLipogenesisMechanistic Target of Rapamycin Complex 2Receptor, ErbB-2TOR Serine-Threonine Kinases

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27015560

Citation

Chen, Yaqing, et al. "MTOR Complex-2 Stimulates acetyl-CoA and De Novo Lipogenesis Through ATP Citrate Lyase in HER2/PIK3CA-hyperactive Breast Cancer." Oncotarget, vol. 7, no. 18, 2016, pp. 25224-40.

Chen Y, Qian J, He Q, et al. MTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget. 2016;7(18):25224-40.

Chen, Y., Qian, J., He, Q., Zhao, H., Toral-Barza, L., Shi, C., Zhang, X., Wu, J., & Yu, K. (2016). MTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. Oncotarget, 7(18), 25224-40. https://doi.org/10.18632/oncotarget.8279

Chen Y, et al. MTOR Complex-2 Stimulates acetyl-CoA and De Novo Lipogenesis Through ATP Citrate Lyase in HER2/PIK3CA-hyperactive Breast Cancer. Oncotarget. 2016 May 3;7(18):25224-40. PubMed PMID: 27015560.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer. AU - Chen,Yaqing, AU - Qian,Jianchang, AU - He,Qun, AU - Zhao,Hui, AU - Toral-Barza,Lourdes, AU - Shi,Celine, AU - Zhang,Xuesai, AU - Wu,Jiang, AU - Yu,Ker, PY - 2016/01/05/received PY - 2016/03/05/accepted PY - 2016/3/26/entrez PY - 2016/3/26/pubmed PY - 2018/1/6/medline KW - ATP citrate lyase KW - breast cancer KW - cancer metabolism KW - lipid synthesis KW - mTORC2 SP - 25224 EP - 40 JF - Oncotarget JO - Oncotarget VL - 7 IS - 18 N2 - The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27015560/mTOR_complex_2_stimulates_acetyl_CoA_and_de_novo_lipogenesis_through_ATP_citrate_lyase_in_HER2/PIK3CA_hyperactive_breast_cancer_ DB - PRIME DP - Unbound Medicine ER -