Introduction of Autophagy
In 1992, Ashford and Porter observed in human liver cells that the cytoplasm, organelles and proteins that need to be degraded are encapsulated by a bilayer membrane to form autophagosomes, which fuse with lysosomes to form autophagosomes and degrade them. This phenomenon is called autophagy. Autophagy is widely present in eukaryotic cells and is a self-protective mechanism of cells. Under normal conditions, the level of autophagy in the cells is low, and the level of autophagy in the cells is rapidly increased under stress conditions. This is beneficial to maintaining the metabolic balance of the protein and alleviating the metabolic pressure, thereby maintaining the stability of the intracellular environment.
The autophagy process is mainly made up of four stages: initiation and extension of autophagic membranes, maturation and degradation of autophagosomes. First, autophagosome-associated proteins recognize parts of cytoplasm, organelles, proteins, and other molecules. Next, the cell membrane of part of the rough endoplasmic reticulum that has not been detached from the ribosome attachment region begins to form an autophagic membrane, also called a barrier membrane. The autophagic membrane gradually extends to encapsulate the components to be degraded to form a closed spherical vesicle, called an autophagosome. Autophagosomes fuse with lysosomes to form autolysosome, which lead to degradation of the membrane and contents of the autophagy, thereby providing energy for intracellular chemical reactions. According to previous studies, researchers have shown that autophagy is closely related to cancer.
The Relationship between Autophagy and Cancer
Autophagy is a conservative metabolic pathway. Loss of essential autophagy results in deleterious accumulation of toxic proteins and damaged organelles, and then it will threaten cell survival. The loss of autophagy will affect the health of cells and the integrity and stability of the genome, leading to diseases such as cancer, aging, liver damage, neurodegenerative diseases and microbial infections. Because autophagy plays a dual role in the development of cancer, it has a very complex function in the development of cancer. Due to the great potential of autophagy in the clinical treatment of cancer, the relationship between autophagy and cancer cells has become a research hotspot.
The researchers first found an allelic deletion of the autophagy gene beclin 1 in many breast, uterine and prostate cancer cells, suggesting that autophagy may have a tumor suppressor effect. Liang et al. re-expressed Beclin 1 protein in breast cancer cells. The cells restore autophagy and inhibit tumorigenesis. The phenomena further confirm that the reduction of autophagy levels will lead to cancer. Studies by Qu et al. have also shown that a decrease in the expression level of autophagy-related genes in normal cells results in a significant increase in the frequency of tumorigenesis. When autophagy-related genes are expressed in cancer cells, cell proliferation is inhibited. The detailed mechanism is not yet fully understood. According to previous research results, its tumor suppressor mechanism may include the following aspects: 1. Autophagy can maintain intracellular metabolic balance, thereby inhibits cancer by reducing DNA damage; 2. Autophagy inhibits cancer by inhibiting abnormal cell proliferation; 3. Autophagy inhibits cancer by inhibiting chronic necrosis of cancer cells.
The first step of carcinogenic transformation of cells involves the regulation of many abnormal signal secretion and autophagy levels. Previous studies have shown that autophagy levels are elevated during cancer development, and autophagy-associated genes in most autophagy-deficient cancer cells often lack only one copy, not a complete deletion. All of these indicate that autophagy is likely to play a dual role in the development of cancer. This means that autophagy may also promote cancer except inhibition. Studies have shown that autophagy can promote cancer cells to adapt stress. Tumor tissue lacks nutrients, oxygen, growth factors, etc. due to long-term ischemia. High levels of autophagy in cancer cells provide important intermediate metabolites for cancer cell survival. Inhibition of autophagy in cancer cells leads to a decrease in the growth rate of these cells in vitro and a metabolic disorder. Interestingly, high levels of autophagy were not observed in vascular-rich tumors. On the other hand, metabolites and some secretions of cancer cells with fewer blood vessels cannot be removed periodically by blood circulation, and autophagy is required to remove these harmful substances. So autophagy also facilitates the survival and metastasis of cancer cells. Before angiogenesis, cancer cells have insufficient nutrient and oxygen supply. Cancer cells respond to stress by entering an apoptotic pathway or necrosis. Owing to the presence of autophagy, the process of apoptosis or necrosis can be delayed. Under severe necrosis conditions, T cells and NK cells clear necrotic cancer cells, while chronic damage does not. Chronic necrosis stimulates the immune system and triggers an inflammatory response. The inflammatory response provides a suitable microenvironment for tumorigenesis, which in turn accelerates cancer cell proliferation. Studies have shown that autophagy also inhibits the apoptosis of cancer cells when they metastasize, which in turn promotes the metastasis of cancer. In addition, during tumorigenesis, autophagy of the cells is enhanced by promoting oxidative stress of the surrounding fibroblasts and other stromal cells. Due to the bystander effect, the process will increase the levels of autophagy in cancer cells, and increase the tolerance of cells to high levels of reactive oxygen, thereby promoting cancer cell survival.
Clinical Significance of Autophagy
The study of the relationship between autophagy and cancer cell metabolism has important guiding significance for the clinical research of cancer. Both cancer chemotherapy and radiotherapy induce cancer autophagy in cancer treatment. Since autophagy is a ubiquitous mechanism in eukaryotic cells, it is relatively safe to perform cancer adjuvant therapy by drug inhibition and induction of autophagy. However, since autophagy has a dual role, and how to regulate autophagy, thereby improve the clinical treatment effect is inconclusive. The regulation of autophagy will inevitably have a potential effect, and both drug therapy and gene therapy will have multiple effects on cells. Therefore, even if the effect of short-term autophagy regulation is significant, the safety of long-term treatment should be carefully monitored. However, with the deepening of research, the use of drug intervention in autophagy may become an important means of cancer treatment and prevention.