Regulation of mTOR by phosphatidic acid.

mTORC1, the mammalian target of rapamycin complex 1, is a key regulator of cellular physiology. The lipid metabolite phosphatidic acid (PA) binds to and activates mTORC1 in response to nutrients and growth factors. We review structural findings and propose a model for PA activation of mTORC1.

Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

Correction to: Late Neogene evolution of the Peruvian margin and its ecosystems: a synthesis from the Sacaco record.

[This corrects the article DOI: 10.1007/s00531-021-02003-1.].

Cancer cells with defective RB and CDKN2A are resistant to the apoptotic effects of rapamycin.

Inhibition of mammalian target of rapamycin complex 1 (mTORC1) with rapamycin in the absence of transforming growth factor-β (TGFβ) signaling induces apoptosis in many cancer cell lines. In the presence of TGFβ, rapamycin induces G cell cycle arrest; however, in the absence of TGFβ, cells do not arrest in G and progress into S-phase where rapamycin is cytotoxic rather than cytostatic. However, we observed that DU145 prostate and NCI-H2228 lung cancer cells were resistant to the cytotoxic effect of rapamycin.

Albumin promotes the progression of fibroblasts through late G into S-phase in the absence of growth factors.

G cell cycle progression is controlled largely by growth factors in early G indicating that it is appropriate to divide and by nutrients in late G indicating sufficient raw material for cell division. We previously mapped a late G cell cycle checkpoint for lipids upstream from a mammalian target of rapamycin complex 1 (mTORC1)-mediated checkpoint and downstream from a mid-G checkpoint known as the Restriction point. We therefore investigated a role for lipids in progression through late G into S-phase.

Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids.

Mammalian target of rapamycin complex 1 (mTORC1) promotes cell growth and proliferation in response to nutrients and growth factors. Amino acids induce lysosomal translocation of mTORC1 via the Rag GTPases. Growth factors activate Ras homolog enriched in brain (Rheb), which in turn activates mTORC1 at the lysosome.

(-)-Oleocanthal and (-)-oleocanthal-rich olive oils induce lysosomal membrane permeabilization in cancer cells.

(-)-Oleocanthal (oleocanthal) is a phenolic compound found in varying concentrations in extra virgin olive oil oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal, as well as naturally oleocanthal-rich extra virgin olive oils, induced damage to cancer cells' lysosomes leading to cellular toxicity in vitro and in vivo.

Glutamine as an Essential Amino Acid for KRas-Driven Cancer Cells.

Cancer cells consume glutamine, a nonessential amino acid (NEAA), at exceedingly high rates to fulfill their energetic and biosynthetic requirements for proliferation. Glutamine plays distinct roles from essential amino acids in cell cycle progression and in the activation of mammalian target of rapamycin (mTOR). Furthermore, the need of cancer cells for glutamine can be exploited therapeutically - especially those driven by KRas.

Early Miocene CO estimates from a Neotropical fossil leaf assemblage exceed 400 ppm.

Premise Of The Study: The global climate during the early Miocene was warmer than the present and preceded the even warmer middle Miocene climatic optimum. The paleo-CO records for this interval suggest paradoxically low concentrations (<450 ppm) that are difficult to reconcile with a warmer-than-present global climate.

Methods: In this study, we use a leaf gas-exchange model to estimate CO concentrations using stomatal characteristics of fossil leaves from a late early Miocene Neotropical assemblage from Panama that we date to 18.

Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine.

Glutamine is a key nutrient required for sustaining cell proliferation, contributing to nucleotide, protein, and lipid synthesis. The mTOR complex 1 (mTORC1) is a highly conserved protein complex that acts as a sensor of nutrients, relaying signals for the shift from catabolic to anabolic metabolism. Although glutamine plays an important role in mTORC1 activation, the mechanism is not clear.

Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes.

Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking activation of the androgen receptor by androgens. Androgen deprivation therapy can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation.

Lipid sensing by mTOR complexes via synthesis of phosphatidic acid.

mTOR, the mammalian target of rapamycin, integrates growth factor and nutrient signals to promote a transformation from catabolic to anabolic metabolism, cell growth, and cell cycle progression. Phosphatidic acid (PA) interacts with the FK506-binding protein-12-rapamycin-binding (FRB) domain of mTOR, which stabilizes both mTOR complexes: mTORC1 and mTORC2. We report here that mTORC1 and mTORC2 are activated in response to exogenously supplied fatty acids via the synthesis of PA, a central metabolite for membrane phospholipid biosynthesis.

A Late G1 Lipid Checkpoint That Is Dysregulated in Clear Cell Renal Carcinoma Cells.

Lipids are important nutrients that proliferating cells require to maintain energy homeostasis as well as to build plasma membranes for newly synthesized cells. Previously, we identified nutrient-sensing checkpoints that exist in the latter part of the G phase of the cell cycle that are dependent upon essential amino acids, Gln, and finally, a checkpoint mediated by mammalian target of rapamycin (mTOR), which integrates signals from both nutrients and growth factors. In this study, we have identified and temporally mapped a lipid-mediated G checkpoint.

First North American fossil monkey and early Miocene tropical biotic interchange.

New World monkeys (platyrrhines) are a diverse part of modern tropical ecosystems in North and South America, yet their early evolutionary history in the tropics is largely unknown. Molecular divergence estimates suggest that primates arrived in tropical Central America, the southern-most extent of the North American landmass, with several dispersals from South America starting with the emergence of the Isthmus of Panama 3-4 million years ago (Ma). The complete absence of primate fossils from Central America has, however, limited our understanding of their history in the New World.

Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells.

During G1-phase of the cell cycle, normal cells respond first to growth factors that indicate that it is appropriate to divide and then later in G1 to the presence of nutrients that indicate sufficient raw material to generate two daughter cells. Dividing cells rely on the "conditionally essential" amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates and as a nitrogen source for nucleotide biosynthesis. We previously reported that while non-transformed cells arrest in the latter portion of G1 upon Q deprivation, mutant KRas-driven cancer cells bypass the G1 checkpoint, and instead, arrest in S-phase.

The Enigma of Rapamycin Dosage.

The mTOR pathway is a critical regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling has been observed in most cancers and, thus, the mTOR pathway has been extensively studied for therapeutic intervention. Rapamycin is a natural product that inhibits mTOR with high specificity.

(-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization.

(-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been implicated in the health benefits associated with diets rich in EVOO. We investigated the effect of OC on human cancer cell lines in culture and found that OC induced cell death in all cancer cells examined as rapidly as 30 minutes after treatment in the absence of serum. OC treatment of non-transformed cells suppressed their proliferation but did not cause cell death.

5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells.

mTOR - the mammalian/mechanistic target of rapamycin - has been implicated as a key signaling node for promoting survival of cancer cells. However, clinical trials that have targeted mTOR with rapamycin or rapamycin analogs have had minimal impact. In spite of the high specificity of rapamycin for mTOR, the doses needed to suppress key mTOR substrates have proved toxic.

Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle.

Mutations in genes encoding regulators of mTOR, the mammalian target of rapamycin, commonly provide survival signals in cancer cells. Rapamycin and analogs of rapamycin have been used with limited success in clinical trials to target mTOR-dependent survival signals in a variety of human cancers. Suppression of mTOR predominantly causes G1 cell cycle arrest, which likely contributes to the ineffectiveness of rapamycin-based therapeutic strategies.

Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways.

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of G1 cell cycle progression. Two key substrates of mTORC1 are ribosomal subunit S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4E-BP1). We reported previously that simultaneous knockdown of S6K and eIF4E causes a transforming growth factor-β (TGF-β)-dependent G1 cell cycle arrest in MDA-MB-231 human breast cancer cells.

Reciprocal regulation of AMP-activated protein kinase and phospholipase D.

AMP-activated protein kinase (AMPK), a critical sensor of energy sufficiency, acts as central metabolic switch in cell metabolism. Once activated by low energy status, AMPK phosphorylates key regulatory substrates and turns off anabolic biosynthetic pathways. In contrast, the mammalian/mechanistic target of rapamycin (mTOR) is active when there are sufficient nutrients for anabolic reactions.

Inhibition of fatty acid synthase induces pro-survival Akt and ERK signaling in K-Ras-driven cancer cells.

Cancer cells with constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation have been associated with overexpression of the lipogenic enzyme fatty acid synthase (FAS) as a means to provide lipids necessary for cell growth. In contrast, K-Ras-driven cancer cells suppress utilization of de novo synthesized fatty acids and rely on exogenously supplied fatty acids for cell growth and membrane phospholipid biosynthesis. Consistent with a differential need for de novo fatty acid synthesis, cancer cells with activated PI3K signaling were sensitive to suppression of FAS; whereas mutant K-Ras-driven cancer cells continued to proliferate with suppressed FAS.

Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT).