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.
Highlights
The mechanistic target of rapamycin acts through two multiprotein complexes, mTOR complex-1 and mTOR complex-2, coordinates signals from growth factors, nutrients and energetics. mTOR functions both in parallel and downstream of the PI3K/AKT signaling pathway that is frequently dysregulated in cancer and a subject of intense discovery research [1, 2]
Because ATP citrate lyase (ACL) produces cytosolic lipogenic precursor acetyl-CoA, we explored whether mTOR regulates ACL in insulinlike growth factor-1 (IGF-1)-stimulated de novo lipid synthesis
More recent studies have suggested an essential role of mTOR complex-2 (mTORC2) in cellular transformation driven by oncogenic HER2 [32] or EGFRvIII [33]
Summary
The mechanistic target of rapamycin (mTOR) acts through two multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2), coordinates signals from growth factors, nutrients and energetics. mTOR functions both in parallel and downstream of the PI3K/AKT signaling pathway that is frequently dysregulated in cancer and a subject of intense discovery research [1, 2]. The mechanistic target of rapamycin (mTOR) acts through two multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2), coordinates signals from growth factors, nutrients and energetics. Activating-mutations within mTOR itself exist in multiple cancer types and may predict therapeutic response to mTOR-targeted therapy [3, 4]. While clinical use of mTORC1 inhibitor rapalog therapy (e.g. temsirolimus, everolimus) validated mTOR as a cancer target, the effectiveness of these drugs may be limited due to resistance to mTORC2 [5, 6]. It is thought that targeting of mTORC1 and mTORC2 with mTOR-KIs will facilitate further dissection of molecular mechanism of mTOR complexes in cancer and a variety of age-related diseases
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