The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions (e.g., cancer). Indeed, they are so interconnected that, in a certain sense, they could be regarded as a single, unique pathway. In this paper, after a general overview of the biological significance and the main components of these pathways, we address the present status of the development of specific PI3K, Akt, and mTOR inhibitors, from already registered medicines to novel compounds that are just leaving the laboratory bench.

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Targeting PI3K/Akt/mTOR Signaling in Cancer.

Abnormalities in ovarian function, including defective oogenesis and folliculogenesis, represent a key female reproductive deficiency. Accumulating evidence in the literature has shown that the PI3K/PTEN/Akt and TSC/mTOR signaling pathways are critical regulators of ovarian function including quiescence, activation, and survival of primordial follicles, granulosa cell proliferation and differentiation, and meiotic maturation of oocytes. Dysregulation of these signaling pathways may contribute to infertility caused by impaired follicular development, intrafollicular oocyte development, and ovulation. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/Akt and TSC/mTOR pathways during mammalian oogenesis and folliculogenesis and their association with female infertility.

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PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update.

Apoptosis occurs frequently in myocardial infarction, oxidative stress injury, and ischemia/reperfusion injury, and plays a pivotal role in the development of heart diseases. Inhibition of apoptosis alone does not necessarily lead to meaningful rescue in terms of either cardiomyocyte survival or function. Activation of the PI3K/Akt signaling pathway induced by insulin not only inhibits cardiomyocyte apoptosis but also substantially preserves and even improves regional and overall cardiac function. Insulin can protect cardiomyocytes from apoptosis by regulating a number of signaling molecules, such as eNOS, FOXOs, Bad, GSK-3β, mTOR, NDRG2, and Nrf2, through activating PI3K and Akt. This review focuses on the protective mechanisms and targets of insulin identified in the prevention and treatment of myocardial injury.

The Cardioprotection of the Insulin-Mediated PI3K/Akt/mTOR Signaling Pathway

AUTHOR COPY ONLY PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update

Little is known about the role of mTOR signaling in plasma cell differentiation and function. Furthermore, for reasons not understood, mTOR inhibition reverses antibody-associated disease in a murine model of systemic lupus erythematosus. Here, we have demonstrated that induced B lineage-specific deletion of the gene encoding RAPTOR, an essential signaling adaptor for rapamycin-sensitive mTOR complex 1 (mTORC1), abrogated the generation of antibody-secreting plasma cells in mice. Acute treatment with rapamycin recapitulated the effects of RAPTOR deficiency, and both strategies led to the ablation of newly formed plasma cells in the spleen and bone marrow while also obliterating preexisting germinal centers. Surprisingly, although perturbing mTOR activity caused a profound decline in serum antibodies that were specific for exogenous antigen or DNA, frequencies of long-lived bone marrow plasma cells were unaffected. Instead, mTORC1 inhibition led to decreased expression of immunoglobulin-binding protein (BiP) and other factors needed for robust protein synthesis. Consequently, blockade of antibody synthesis was rapidly reversed after termination of rapamycin treatment. We conclude that mTOR signaling plays critical but diverse roles in early and late phases of antibody responses and plasma cell differentiation.

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mTOR has distinct functions in generating versus sustaining humoral immunity

The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review “PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle” we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.

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The Paradox of Akt-mTOR Interactions.

Antoine Lavoisier (eighteenth century) demonstrated that living organisms consume oxygen to slowly burn the fuels in their bodies to release energy (1). Louis Pasteur (2) in an epoch making discovery, recognized as “the Pasteur effect,” declared “fermentation is an alternate form of life and that fermentation is suppressed by respiration” [reviewed in (3–5)]. Yet another observation of Pasteur, that yeast cells consume oxygen to multiply, is debated less among cancer biologists. This nevertheless, forms the first scientific observation that proliferating cells need oxygen to divide. Pasteur was involved in a path breaking debate with Liebig on whether fermentation is a chemical or a biological process? By 1880s Pasteur could establish that fermentation is a physiological process, and oxygen, considered to be a putrefying factor by Liebig and others, was a growth promoting factor [reviewed in (3)]. Six decades later, Warburg (6) proposed that damaged respiration and enhanced fermentation of glucose is the prime cause of cancer formation. It became popular as “aerobic glycolysis” and a counter to “the Pasteur effect.” Warburg was uncompromising and was intolerant to any alternate theory on cancer formation and declared to the German Central Committee for Cancer control in 1955 at Stuttgart “… there is today no other explanation for the origin of cancer cells, either special or general. From this point of view, mutation and carcinogenic agent are not alternatives, but empty words, unless metabolically specified…” (7). Crabtree (8), a contemporary of Warburg, suggested that pathological over growths use aerobic glycolysis as a source of energy and glucose uptake and glycolytic activity has a depressive effect on oxygen consumption. His conclusion gained the popularity as the “inverted Pasteur effect” or the “Crabtree effect” (9). Several authors in the middle of twentieth century reported that glucose is a negative regulator of respiration. These reports indicate that there is an initial stimulation of oxygen consumption for about 20–120 s following glucose consumption followed by an inhibitory period, which after equilibration stabilizes to a constant of about 30% of the endogenous rate until all the glucose was consumed [reviewed by (9)].

https://www.sisd.net/cms/lib/TX01001452/Centricity/Domain/1297/Did%20we%20get%20Pasteur%20Warburg%20and%20Crabtree%20on%20a%20right%20note.pdf

Abhinandita Dash

Papers

The Paradox of Akt-mTOR Interactions.

Did We Get Pasteur, Warburg, and Crabtree on a Right Note?