PI3K-AKT-mTOR signaling pathway in cancer
The carcinogenesis transformation of cells into malignant tumors emanates from the interaction between various multiple signal transduction pathways. The PI3K/Akt/mTOR signal pathway is activated in tumorigenesis, making it pivotal in the process (Xu et al., 2020). The pathway is also critical in the survival, proliferation, metastasis, and invasion of the malignant cells. The attempts to inhibit this pathway has been the hallmark of cancer therapeutic efforts.
The PI3K/Akt/mTOR signaling pathway, as discussed earlier, is at the center of the cell cycle and growth. The numerous downstream molecules in the pathway phosphorylate the mTor activating it in the process. This, in turn, results in the binding of cyclin D1 into the cyclin dependent kinase (CDK), which promotes cell division. Cyclin D expression in high amounts can induce cell cycle transition from the G1 to S phase, shortening the cycle and increasing the rate of cancer cell transformation. Xu et al. (2020) note that the CDK inhibitor p27kip1 negatively regulates the cell cycle where it inhibits CDK activity in the process resulting in cell cycle arrest and halting of cell proliferation. AKT inhibits this process by phosphorylating the 17kip1 protein hence promoting cell proliferation and differentiation. Furthermore, mTOR helps in the regulation of biological macromolecule synthesis of proteins, lipids, and nucleotides, thus providing an enabling environment for cancer growth (Goncalves & Hopkins & Cantley, 2018)
Angiogenesis forms the primary basis of cancer growth, metastasis, and invasion. The pathway not only regulates cell proliferation, growth, and death, but it is also at the heart of both normal and tumor angiogenesis (Goncalves & Hopkins & Cantley, 2018). Activated AKT results in eNOS distribution in the vascular endothelium through the phosphorylation of Ser177, which results in the production of nitric oxide in the blood vessels. This helps in the regulation of vascular function and vasodilation, vascular remodeling, and angiogenesis. AKT activation also results in the expression of elevated HIF-1, which is a crucial regulator of angiogenesis that up-regulates the expression of VEGF and other angiogenic factors. (Xu et al., 2020). They further note that the HIF-1 affects the vascular endothelial cells in the following ways: Firstly, It promotes the proliferation and migration of endothelial cells. It increases the vascular endothelium’s permeability, promoting protein exosmosis and cellulose scaffold, which help vascular endothelial cells migrate and have vascular growth. Finally, it activates the proteolytic enzyme system that degrades the extracellular matrix, promoting angiogenesis in the process.
Goncalves, Hopkins, and Cantley (2018) note that PI3K/AKT/mTOR signaling pathway is also at the heart of cancer cell invasion and metastasis through a number of mechanisms: First, it activates the AKT, which enhances the transcriptional activity of NF-kappa B that promotes the transport of tumors supporting tumor invasion in the process. Secondly, it promotes Actin polarization.AKT1, a downstream molecule of PI3K, is involved in regulating the invasion and metastasis of breast cancer cells Goncalves, Hopkins & Cantley (2018). The actin-related protein, Palladin, is involved in skeleton construction and regulation of the actin system structure, key in cell migration.AKT1 can phosphorylate Ser507 of Palladin to regulate the cancer cells metastasis and invasion activity. Finally, the pathway activates the matrix metalloproteinases (MMPs), a group of proteolytic enzymes that participate in the degrading of the extracellular matrix in promoting invasion and metastasis (Xu et al.,2020).
PI3K/AKT/mTOR pathways are important in tumorigenesis and cancer development. Up-regulation signals through growth factors result in AKT activation, which further downstream the regulators of cell proliferation, invasion, angiogenesis, and metastasis. Blocking of this signal brings about an antitumor effect forming the basis of anti-cancer treatment.
Role of PI3K/AKT/mTOR in neurodegenerative disease
Alzheimer’s disease
Alzheimer’s disease is characterized by memory impairment, agnosia, impaired visual-spatial skills, personality, behavioral changes, and executive dysfunction. It is the most significant neurodegenerative disease resulting from neuronal and synaptic damage (Xu et al., 2020). Tau protein is important in the assembly of microtubules and the overall structural integrity of the neurons. Tau protein abnormality through over phosphorylation and aggregation results in microtubule instability and neurofibrillary tangle (NFT) formation leading to neuronal death and senile plaques (Xu et al., 2020). This is pathognomonic in Alzheimer’s disease.
AKT mediates the phosphorylation of Thr212 and Ser214 in the Tau protein, a process catalyzed by PI3K-PDK. Increased PIP3 in the membrane results in colonization of the AKT-PDK1 with the PH domain, resulting in the activation of kinase-mediated phosphorylation (Xu et al., 2020). This activation induces AKT activation, which inhibits GSK-3beta protein, which is important in Tau phosphorylation. A disorder in the signaling pathway increases the GSK-3beta activity resulting in TAU hyperphosphorylation and subsequent NFT formation. The amyloid-beta chain has also been shown to interact with the signaling pathway. Abeta executes its neurotoxic activity by inhibiting the PI3K/AKT/mTOR pathway in neural stem cells and neuronal cells, increasing the TAU hyperphosphorylation.
Parkinson’s disease
Parkinson’s disease is also a common neurodegenerative disease characterized by motor symptoms of tremors, rigidity, and postural instability and non-motor symptoms involving nervous, mental, sensory, and cognitive impairments. According to Xu et al. (2020), studies have shown that AKT plays a role in PD signal transduction. The AKT and phosphorylated form is reduced in the substancia nigra pars compacta of patients with PD. The PI3K/ALT/, mTOR pathway enhances dopamine neurons’ survival and growth by inhibiting apoptosis, therefore preventing PD. Xu et al. (2020) add that studies have suggested the GSK-3 beta is expressed abnormally in PD. The pathway also affects the oxidative pathway through downstream signaling of molecules such as FoxO3a. This results in oxidative stress, which predisposes to PD. According to Xu (2020), the signaling pathway can affect signal transduction in patients with PD through the downstream modulation of proteins molecules targeted by GSK-3beta, mTOR, and FoxO3a. This pathway has also been shown to play a role in developing Huntington’s disease characterized by irregular muscle twitching and involuntary and purposeless movements.
PI3K pathway and Diabetes
Huang et al. (2018) state that studies have shown that AKT regulates glucose and lipid metabolism. Activated AKT2 is expressed in insulin-responsive tissues and has been shown to promote the translation of GLUT4, the glucose transporter. AKT has been shown to facilitate glycolysis of Glucose 6-phosphate and glycogen synthase kinase to produce energy and promote glycogen production. The PI3K/AKT pathway regulates glucose metabolism through GSK-3 and FoxO1 (Świderska et al., 2020)
In the skeletal muscle, insulin uses the pathway to regulate metabolism by promoting glucose transport and protein synthesis. Given that approximately ninety percent of insulin-stimulated glucose is used in the skeletal muscle, the pathway plays a critical role in glucose metabolism and homeostasis. The interference of AKT reduces insulin initiated glucose uptake in the muscle. AKT phosphorylates AS160 in the process inducing GLUT4 translocation, which facilitates the transport of glucose into storage vesicles for glycogenesis to take place (Huang et al., 2018). Impairment of the insulin-AKT pathway results in insulin resistance in the skeletal muscle resulting in hyperglycemia and subsequent development of type 2 diabetes. Obesity is also likely to follow. In the adipose tissue, the insulin-AKT pathway regulates adipose tissues’ metabolism by increasing glucose utilization, protein synthesis, and lipogenesis (Huang et al., 2018). Insulin enhances glucose utilization in adipose tissues. Derangement in this pathway results in obesity and hyperglycemia.
The PI3K/AKT pathway also has activity in the liver. The majority of extracellular glucose is produced in the liver and kidney, yet it is only the liver that responds to insulin activity (Świderska et al., 2020). In the fasting state, the liver increases glucose levels through gluconeogenesis and glycogenolysis. In the fed state, the PI3K/AKT pathway reduces the liver’s above mechanisms of glucose production. Instead, it increases glycogen synthesis and lipogenesis as well as increased glucose production in other tissues. Derangements in this pathway alter the hemostasis of metabolism, resulting from typing two Diabetes and obesity. Huang et al. (2018), manipulation of PI3K/AKT pathway signaling and the downstream of molecules is the basis for developing therapeutic agents in type 2 diabetes and obesity.