AKT, also known as Protein Kinase B, is a central regulatory enzyme within human cells. It orchestrates fundamental life processes, integral to cell growth, survival, and adaptation. Understanding AKT is key to comprehending both healthy cellular function and the origins of various diseases.
AKT’s Essential Roles in Healthy Cells
AKT plays a central role in maintaining the normal functions of healthy cells, particularly in regulating cell survival, growth, and metabolism. It ensures that cells behave as they should, responding appropriately to internal and external signals.
AKT promotes cell survival by inhibiting programmed cell death, known as apoptosis. It achieves this by phosphorylating and inactivating proteins that typically promote cell death, such as Bad and certain caspases. This action helps cells persist and maintain mitochondrial integrity, preventing the release of factors that trigger cell death pathways.
Beyond survival, AKT stimulates cell growth and proliferation. It influences proteins like the mechanistic Target of Rapamycin (mTOR) complex 1 (mTORC1), a key regulator of protein synthesis. By activating mTORC1, AKT promotes increased cell size and overall cellular biomass. It also contributes to cell cycle progression by phosphorylating cell cycle inhibitors like p21 and p27, allowing cells to divide and multiply.
AKT regulates cellular metabolism, specifically impacting glucose uptake and utilization. Activated AKT facilitates the movement of glucose transporters, such as GLUT4, to the cell surface, enabling cells to absorb more glucose. It influences enzymes like glycogen synthase kinase 3 (GSK3) to promote glycogen production, ensuring a steady energy supply for cellular functions.
When AKT Goes Wrong
The precise regulation of AKT is important for cellular health. Its dysregulation, through overactivity or underactivity, can contribute to the development and progression of numerous diseases, including cancer and metabolic disorders.
Overactive AKT is a common feature in many cancers, promoting uncontrolled cell growth, survival, and spread. As an oncogene, AKT’s persistent activation allows cancer cells to evade programmed cell death, proliferate excessively, and metastasize. Aberrant activation of the PI3K/AKT pathway, often due to mutations or amplifications, is found in approximately 39% of diverse human cancers, including breast, ovarian, and prostate cancers.
In metabolic diseases, particularly insulin resistance and type 2 diabetes, AKT’s malfunction impairs glucose metabolism. Insulin typically activates AKT to facilitate glucose uptake into cells; however, in insulin resistance, this signaling pathway is disrupted. This impairment reduces the ability of cells to absorb glucose, leading to elevated blood sugar levels characteristic of diabetes. This dysregulation can create a cycle where insulin resistance exacerbates the PI3K/AKT pathway imbalance.
AKT dysregulation also plays a role in some neurological disorders. While the mechanisms are complex, imbalances in AKT signaling have been implicated in conditions like Alzheimer’s and Parkinson’s disease. For instance, increased phosphorylated AKT levels have been observed in Alzheimer’s disease, suggesting a potential link to disease progression. Maintaining proper AKT activity in the nervous system is important for neuronal function and survival.
Targeting AKT for Health
Understanding AKT’s intricate roles in health and disease has paved the way for developing new therapeutic strategies. Scientists and doctors are exploring ways to modulate AKT activity to treat various conditions, particularly those where its function is abnormal. This research holds promise for more targeted and effective interventions.
In cancer treatment, AKT inhibitors are being explored to block the overactive pathway that drives tumor growth. These drugs aim to counteract the effects of hyperactive AKT, forcing cancer cells to undergo programmed cell death or stop proliferating. Several AKT inhibitors, such as ipatasertib and capivasertib, are currently in clinical trials for different cancer types, including breast, prostate, and ovarian cancers.
The concept of personalized medicine is becoming increasingly relevant in AKT-targeted therapies. Identifying specific mutations in AKT or its associated pathways in a patient’s tumor can help tailor treatment approaches. For example, some AKT inhibitors show greater effectiveness in tumors with particular genetic alterations in the PI3K/AKT pathway. This allows for a more precise selection of patients who are most likely to benefit from these targeted drugs.
Research continues to advance the understanding and application of AKT-targeted therapies. Efforts are focused on developing more potent and selective inhibitors, as well as exploring combination therapies to enhance efficacy and overcome potential drug resistance. The future of AKT research involves extending these targeted approaches to other diseases where AKT dysregulation is a contributing factor, offering new avenues for improving patient outcomes.