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Autophagy and cancer
Often times, cancer occurs when several different pathways that regulate cell differentiation are disturbed. Autophagy plays an important role in cancer – both in protecting against cancer as well as potentially contributing to the growth of cancer. Autophagy may protect against cancer by isolating damaged organelles, allowing cell differentiation, increasing protein catabolism, and even promoting cell death of cancerous cells. However, autophagy can also contribute to cancer by promoting survival of tumor cells that have been starved. The role of autophagy in cancer is one that has been highly researched and reviewed. There is evidence that emphasizes the role of autophagy both as a tumor suppressor as well as a factor in tumor cell survival. However, recent research has been able to show that autophagy is more likely to be used as a tumor suppressor according to several models.

Gene & Protein Regulation
Autophagy is initiated by the ULK1 kinase complex. This complex consists of ULK1, Atg13, Atg17, and receives stress signals from mTOR complex 1. Once the mTORC1 kinase activity is inhibited, autophagosome formation occurs. This involves Vps34 which forms a complex with Beclin1 after interacting with Ambra, Bif1, and Bcl-2 which module its binding properties. Binding to Vps34 is essential because of its lipid kinase activity. Autophagosome formation also requires Atg12 and LC3, protein conjugation systems that resemble ubiquitin. The LC3 system is important for transport and maturation of the autophagosome. Once an autophagosome has matured, it fuses its external membrane with lysosomes to degrade its cargo. Depending on the location of the p53 tumor suppressor protein, it plays a different role in regulating autophagy as well. When in the nuclear region, p53 acts as a transcription factor in order to activate DRAM1 and Sestrin2 which activates autophagy. In the cytoplasm, p53 inhibits autophagy. Thus, to induce autophagy, p53 is degraded through proteasomes.

Tumor Suppressor In order to maintain homeostasis conditions, autophagy must not be disrupted. If this important mechanism is interrupted, tumor growth can likely occur. The main function of autophagy in tumor suppression is its ability to remove damaged proteins and organelles thus limiting any cell growth instability [9]. Several experiments have been done with mice and varying Beclin1, a protein that regulates autophagy. When the Beclin1 gene was altered to be heterozygous (Beclin 1+/-), the mice were found to be tumor prone [10]. However, when Beclin1 was overexpressed, tumor development was inhibited [11]. Another study done on p62 further emphasizes autophagy’s role in tumor suppression. The increase of p62/SQSTM 1 protein groups due to lack of autophagy, damaged mitochondria, and defected misfolded proteins lead to reactive oxygen species (ROS) production [9]. ROS leads to damaged DNA and thus the formation of unwanted tumor cells [9]. Necrosis and chronic inflammation also has been shown to be limited through autophagy which helps protect against the formation of tumor cells. Thus these experiments shown autophagy’s role as a tumor suppressor [12].

Tumor Cell Survival Alternatively, autophagy has also been shown to play a huge role in tumor cell survival. In cancerous cells, autophagy is used as a way to deal with stress on the cell [14]. Once these autophagy related genes were inhibited, cell death was potentiated [13]. Tumor cells have high metabolic demands due to the increase in cell proliferation [9]. The increase in metabolic energy is offset by autophagy functions. These metabolic stresses include hypoxia, nutrient deprivation, and an increase in proliferation. These stresses activate autophagy in order to recycle ATP and maintain survival of the cancerous cells [2]. Autophagy has been shown to enable continued growth of tumor cells by maintaining cellular energy production. By inhibiting autophagy genes in these tumors cells, regression of the tumor and extended survival of the organs affected by the tumors were found [15]. Furthermore, inhibition of autophagy has also been shown to enhance the effectiveness of anticancer therapies [2].

Mechanism of Cell Death Cells that undergo an extreme amount of stress experience cell death either through apoptosis or other mechanisms. Prolonged autophagy activation leads to a high turnover rate of proteins and different organelles. This high rate above the survival threshold may kill cancer cells with a high apoptotic threshold [16]. This technique can be utilized as a therapeutic cancer treatment.

Therapeutic Target New developments in research have found that targeting autophagy may be a viable new therapeutic solution in fighting cancer. As discussed above, autophagy plays both a role in tumor suppression and tumor cell survival. Thus, these qualities about autophagy can be used and manipulated as a strategy for cancer prevention. The first strategy is to induce autophagy and enhance its tumor suppression attributes. The second strategy is to inhibit autophagy and thus induce apoptosis [13]. The first strategy has been viewed and tested by looking at dose-response antitumor effects in autophagy-inducing therapies. These therapies have shown that autophagy extent increases in a dose-dependent manner. This is directly related to the growth of cancer cells in a dose-dependent manner as well [14]. Therefore, this data supports the development of therapies that will encourage autophagy. Inhibiting the proteins pathways directly known to induce autophagy may serve as another anticancer therapy [13]. Lastly, overexpression of autophagy genes can be used [13]. The second strategy is based on the idea that autophagy is a protein degradation system used to maintain homeostasis and the findings that inhibition of autophagy often leads to apoptosis. Inhibition of autophagy is riskier because it may lead to cell survival instead of the desired cell death [14]. This method requires much more testing.