What are the functions of Rapamycin? (II)

  1. PLoS Biol: Scientists reveal new mechanism of Rapamycin.

doi: 10.1371 / journal.pbio.3000252

Recently, in a research report published in PLoS Biology, scientists from the University of Michigan revealed a new pathway of anti-aging drug Rapamycin through research. Researcher Xiaoli Zhang said that the main function of lysosomes is to maintain the healthy state of cells because it can degrade harmful substances in cells. Autophagy can degrade the abnormally functional components of the cells and also provide basic elements for cell survival.

Researchers have long believed that rapamycin can target at least one cellular pathway. Now researchers have found one of these pathways, the calcium channel named TRPML1 on the lysosomal membrane. Related research findings may also help to expand the use of rapamycin. Autophagy is vital to cell health. It can be used as a waste recycling pathway to maintain the quality of proteins and organelles in cells. During natural aging, cells are in culture fluids full of dysfunctional proteins and organelles, especially in the process of neurodegeneration such as Alzheimer’s disease and Parkinson’s disease. Autophagy depends on lysosomal activity. TRPML1, as the main calcium ion channel on lysosome, plays a key role in regulating lysosomal function.

  1. PNAS: New drug delivery system can inhibit tumors by 87%!

doi: 10.1073 / pnas.1817251116

As cancer treatment becomes more complex, we need more sophisticated drug delivery systems that can deliver multiple drugs with different chemical components simultaneously. Now, researchers from Harvard’s John A. Paulson School of Engineering and Applied Science (SEAS) have developed a method to make nano-sized drug delivery vehicles that can deliver multiple drugs simultaneously and is more effective than current methods being used. These new drug delivery vehicles were tested on mice with HER2 breast tumors. Researchers found that combined use of docetaxel, rapamycin, and afatinib at a total dose of 5 and 2.5 mg / kg inhibited 94% and 87% of breast cancer, respectively. Docetaxel is one of the most effective chemotherapy drugs for breast cancer.

Therefore, these hybrid nanocarriers could be used to provide a new combination of anticancer drugs to cancer-bearing mice through intravenous injection. Significant effects has been found on breast tumors. This study enables the use of compounds that were previously undeliverable in cancer treatment and lays the foundation for further development in a wide range of biomedical applications.

  1. Cell Metabol: Rapamycin may be effective in treating certain liver cancers.

doi: 10.1016 / j.cmet.2019.01.002

Recently, in a research report published in Cell Metabolism, scientists from the University of Pittsburgh identified in animal models and patient tissues a new type of molecular pathway in the liver. Rapamycin, a drug commonly used in organ transplantation, may be redirected to treat specific types of liver cancer.

Researcher found that liver cancer with mutations in the β-catenin gene may be more susceptible to rapamycin. This make researchers rethink the possible new uses of rapamycin. It might be a new treatment for liver cancer, especially drug-resistant liver cancer. Researchers have pointed out that a series of cells around the central vein in the liver often carry high levels of mTOR protein. mTOR protein is a very important nutrient and energy sensor for cell metabolism and it exists in the same cells where β-catenin is active.

  1. Cell Death & Differ: Study reveals new mechanism of mitochondrial ROS affecting muscle differentiation through cell autophagy.

doi: 10.1038 / s41418-018-0165-9

In a recent study published in Cell Death & Differentiation, researchers from South Korea found that mitochondrial ROS can stimulate the PI3K/AKT/mTOR cascade signaling pathway, and activated mTORC1 will induce autophagy signaling pathways through phosphorylation of the autophagy initiation factor ULK1 Serine at position 317, and can up-regulate the expression of multiple Atg proteins involved in autophagy to promote muscle differentiation.

The researchers further used the anti-oxidant MitoQ or mTORC1 inhibitor rapamycin, and found that when ROS is eliminated or mTORC1 is inhibited, it will affect the phosphorylation of ULK1 and Atg protein expression. In summary, the study found that mitochondrial ROS can reconstitute the cellular architecture by activating mTOR and inducing cell autophagy during muscle differentiation. This proposed a new regulatory mechanism for mitochondrial ROS to regulate muscle differentiation.

  1. eLife: Scientists find fatal weakness of prostate cancer cells.

doi: 10.7554 / eLife.32213

The missing of the tumor suppressor gene PTEN is very common in prostate cancer. Once this gene is deleted, cancer is likely to occur. A downstream effect of losing PTEN is the increased activation of a protein called protein kinase (Akt). Akt has a variety of functions in cells, including promoting metabolism and cell proliferation, both of which are required by cancer cells and therefore promote uncontrolled growth and spread of cancer cells. Akt’s excessive activation makes cancer cells resistant to chemotherapy, but drug development aimed at suppressing Akt has failed due to toxicity. Akt activation also produces excess reactive oxygen species (ROS), a byproduct of cell metabolism that can damage cellular structures, including DNA.

Researchers from the University of Illinois found that although ROS levels in cancer cells are quite high, which usually help them grow and proliferate. However, ROS levels that exceed a certain threshold can be toxic, which can selectively kill cancer cells without affecting normal cells. To increase ROS levels in cancer cells, they used a natural compound called phenylethyl isothiocyanate (PEITC) to inhibit the ROS clearance factor. In a PTEN-deficient mouse prostate cancer model, PEITC combined with another drug called rapamycin almost completely eliminated tumors. These mice showed no signs of cancer recurrence for 6 months after treatment. Next, the researchers targeted another downstream metabolic pathway that Akt superactivates: an enzyme called hexokinase 2 (HK2). The researchers found that when they knocked out HK2 in a mouse prostate cancer model, the tumors in these mice stopped growing. Researchers have found the same phenomenon in human prostate cancer cells: inactivating HK2 can maintain the sensitivity of prostate cancer cells to chemotherapy.