Oncotarget

Research Papers:

mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer

Yaqing Chen, Jianchang Qian, Qun He, Hui Zhao, Lourdes Toral-Barza, Celine Shi, Xuesai Zhang, Jiang Wu and Ker Yu _

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Oncotarget. 2016; 7:25224-25240. https://doi.org/10.18632/oncotarget.8279

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Abstract

Yaqing Chen1, Jianchang Qian1, Qun He 1, Hui Zhao1, Lourdes Toral-Barza2, Celine Shi2, Xuesai Zhang1, Jiang Wu2 and Ker Yu1

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

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

Correspondence to:

Ker Yu, email:

Keywords: mTORC2, ATP citrate lyase, lipid synthesis, breast cancer, cancer metabolism

Received: January 05, 2016 Accepted: March 05, 2016 Published: March 22, 2016

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.


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