ArticleOncotarget2016
mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 47 citations in OpenAlex.
- Article
- Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.Biomedicines · 2025Article
- AKT kinases as therapeutic targets.Journal of experimental & clinical cancer research : CR · 2024Review
- Micro-RNAs in breast cancer progression and metastasis: A chromatin and metabolic perspective.Heliyon · 2024Review
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4.Oncogene · 2024Article
- Lipid Metabolism as a Potential Target of Liver Cancer.Journal of hepatocellular carcinoma · 2024Review
- Hypoxia-induced epigenetic regulation of breast cancer progression and the tumour microenvironment.Frontiers in cell and developmental biology · 2024Review
- Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction.Nature communications · 2023Article
- Article
- AMPK suppresses Th2 cell responses by repressing mTORC2.Experimental & molecular medicine · 2022Article
- Reprogramming of Fatty Acid Metabolism in Gynaecological Cancers: Is There a Role for Oestradiol?Metabolites · 2022Review
- Lipogenesis inhibitors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2022Review
- NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase.International journal of molecular sciences · 2022Review
- Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.Nature communications · 2021Article
- Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges.Journal of leukocyte biology · 2021Review
- Emerging Roles for AKT Isoform Preference in Cancer Progression Pathways.Molecular cancer research : MCR · 2021Review
- Exploring the Role of ATP-Citrate Lyase in the Immune System.Frontiers in immunology · 2021Review
- The Heterogeneity of Lipid Metabolism in Cancer.Advances in experimental medicine and biology · 2021Article
- Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities.Frontiers in oncology · 2021Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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