title: mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.
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.
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Jianchang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.affiliation: Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Xuesai
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D005260:Female; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001275:ATP Citrate (pro-S)-Lyase; D000105:Acetyl Coenzyme A; D058534:Class I Phosphatidylinositol 3-Kinases; D000076225:Mechanistic Target of Rapamycin Complex 2; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human
keywords: ATP citrate lyase; breast cancer; cancer metabolism; lipid synthesis; mTORC2