AMPK’s double-faced role in advanced stages of prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial–mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors’ expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. (AU)

AMPK's double-faced role in advanced stages of prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.

Aging & COVID-19 susceptibility, disease severity, and clinical outcomes: The role of entangled risk factors.

The emergence of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) in late 2019 has been associated with a high rate of mortality and morbidity. It has been determined that the old population are not only at an increased risk for affliction with COVID-19 infection, but also atypical presentations, severe forms of the disease, and mortality are more common in this population. A plethora of mechanisms and risk factors contribute to the higher risk of infection in the old population. For instance, aging is associated with an increment in the expression of Angiotensin-Converting Enzyme-2 (ACE-2), the receptor for SARS-CoV-2 spike protein, which precipitates replication of the virus in the old population. On the other hand, immune dysregulation and changes in gut microbiota as a result of aging can contribute to the cytokine storm, one of the main indicators of disease severity. Decrement in sex steroids, especially in women, as well as growth hormone, both of which have crucial roles in immune regulation, is a key contributor to disease severity in old age. Senescence-associated oxidative stress and mitochondrial dysfunction in both pneumocytes and immune cells contribute to the severity of infection in an exacerbative manner. In addition, lifestyle-associated factors such as nutrition and physical activity, which are compromised in old age, are known as important factors in COVID-19 infection. Aging-associated comorbidities, especially cardiovascular diseases and diabetes mellitus, also put older adults at an increased risk of complications, and disease severity.