An important and well documented

An important and well-documented pathway involved in cellular growth and proliferation is the mTOR-mediated synthesis of proteins and lipids [7,13,14]. Although found to be tissue specific or context specific regulation, it has always been observed that either one or both the mTOR complexes regulates important anabolic pathways. Much has been discovered about the role of mTOR complex1 (mTORC1) in the context of protein and lipid synthesis [[15], [16], [17]] but recent research indicates that complex 2 is equally important particularly in the context of specific tissues such as the liver [18]. Glutamine can potentially regulate the activity of mTORC1, which opens up many avenues in therapeutic targeting of the mTOR-glutamine nexus. In some cancer cells, excess glutamine is exported in exchange for leucine and other essential amino acids thereby activating mTOR [19]. mTOR is a central component of the key energy signaling network-the PI3K-Akt-mTOR pathway which harbors a common lesion in many human cancers [[19], [20], [21]]. Conversely intracellular levels of glutamine and leucine support glutaminolysis, promoting lysosomal translocation and mTOR activation [22,23]. mTORC1 activation regulates glutamate dehydrogenase (GDH) thereby launching a robust anabolic response through glutamine catabolism [24]. mTORC1 and Myc have also been suggested to act as central regulators of glutaminolysis where mTORC1 regulates glutaminase (GLS)1 expression through S6 K1/eIF4B substrates via Myc-dependent activation [20,25] thereby linking glutamine catabolism directly to mTOR activation. Recent research has described how amino BW 723C86 hydrochloride unavailability inhibits mTOR activity thereby activating autophagy to fuel bioenergetics [22]. Remarkably, the mTORC1 pathway has been shown to have opposing effects on cell proliferation depending on the amino acid availability. During condition of nutrient scarcity, mTORC1 inhibition results in increased autophagy and enhancing cell proliferation [26]. These data may provide key insights in the current mechanism of interplay between glutamine and cell signaling in cancer that needs further investigation. Therefore, here, we investigated the effect of mTOR inhibition along with glutamine deficiency on cancer cell survival. Our data reveals how under conditions of mTOR inhibition glutamine starvation induces rescue of Akt by upregulating autophagy and thus aiding in cancer cell survival.
Results & discussion
Experimental procedures
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Introduction Phagocytosis by macrophages is the cornerstone of the innate immune response, which eliminates invading pathogens, cellular debris, and foreign bodies. Several phagocytic receptors including Fcγ receptors, the complement receptor, integrins such as α5β1 and αvβ3, the lipopolysaccharide (LPS) receptor CD14, and the mannose receptor are involved in the phagocytic uptake of particles [1], [2], [3], [4]. The binding of pathogens or specific molecules by these receptors results in the rapid responses of a series of intracellular signaling proteins, including the Rho family of G proteins, which play an important role in the reorganization of the actin cytoskeleton [1], [3]. Recent studies have reported that several kinases including p38 mitogen-activated protein kinase (MAPK) or AMP-activated protein kinase can activate Rac1, a subfamily of the Rho family, which plays a pivotal role in the phagocytic uptake of particles [5], [6], [7], [8]. Previous studies have revealed that the activation of p38 MAPK can regulate actin cytoskeletal reorganization, which plays an important role in phagocytosis, cell migration, and morphological changes in various cell populations [9], [10], [11]. Specifically, p38 MAPK activation by various stimuli enhances the ability of macrophages to phagocytose bacteria [7], [11], [12], [13], [14]. Stimulation of toll-like receptors (TLRs) with specific ligands enhances bacterial phagocytosis by macrophages and was blocked by p38 MAPK inhibitors or small-interfering RNA (siRNA)–mediated knockdown of p38 MAPK [11], [13]. Deprivation of nutrients, such as amino acids or glucose, has been shown to increase the phosphorylation of p38 MAPK, which is required for the starvation-induced increase in macrophage bacterial phagocytosis [12].