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About the author: Ruyi Li is a student of Beijing National Day High School, and her interested fields are medicine, cancer and etc.
Mechanisms and Roles of Autophagy in Colon Cancer
Ruyi Li International Department, Beijing National Day School, Beijing, 100089, P .R. China
Abstract: Autophagy, a crucial mechanism for cellular components breakdown and renewal, has been intensively researched in the medical field in recent years. Autophagy-related genes, proteins, and pathways play an important role in the growth, reproduction, and metastasis of tumor cells. In colorectal cancer (CRC), mutation of autophagy-related genes may result in the progression of the disease or effective control of metastasis. Some chemicals can increase or inhibit normal autophagy levels in cells, thus controlling the growth of the tumor. These chemicals are potential drugs that are also possible to help design target therapies for CRC patients. This review aims to summarize situations that which autophagy is triggered by any cancer-related signal and leads to different results.
Keywords: Autophagy; Colorectal cancer; Carcinogenesis; Inflammation; Tumor growth; Metastasis
DOI: 10.47297/taposatWSP2633-456932.20220303
1. Introduction
Colorectal cancer (CRC) is the third most commonly diagnosed and the second most fatal malignancy worldwide [1]. In the US, it is the third leading cause of cancer-related deaths [2]. Current treatments include surgery, chemotherapy, and immunotherapy. Targeted drugs are involved, but the number of targeted drugs is limited. Therefore, the development of targeted therapies for CRC is still an urgent need in the world. Autophagy is the process of cellular materials being degraded in lysosomes [3]. It has dual roles in carcinogenesis, tumor cell growth, and metastasis [4]. Since autophagy involves the breakdown of toxic or impaired cellular components in tumors, it can prevent cell apoptosis and allow the tumor to grow and metastasize; but in other cases, the activation of autophagy also triggers cell apoptosis, which results in atrophy of the tumor and better prognosis of patients. The decisive biological factor that decides whether autophagy plays a positive or
Theory and Practice of Science and Technology
negative role in CRC treatment is still unclear and deserves further investigation. This paper aims to discuss the role of autophagy in colon cancer from a more comprehensive angle, involving as many sit
uations as possible.
2. Autophagy in Tumerigenesis of CRCreactive materials studies
The effects of autophagy on tumorigenesis are different according to the different stages of tumorigenesis. At the beginning of the transformation of normal cells to cancer cells, lack of autophagy can induce tumorigenesis[5-8]; while in the stage of transformation of benign tumor cells to malignant tumor cells, a low level of autophagy inhibits this transformation[9-15]. Colon inflammation also contributes to tumerigenesis[16-19].
(1) Low Level of autophagy induces tumorigenesis
Autophagy happens in both normal cells and cancer cells, so it is difficult to determine whether this cellular activity was one of the leading causes of forming a lesion in the tissue or organ level before the turn of the 20th century. Back in 1999, the role of Beclin 1 binding with Bcl-2 as a negative regulator of tumorigenesis and its ability to induce autophagy were examined shown in Fig. 1[5]. In 2007, Bif-1 was found to be a positive regulator of Beclin 1 and bind to Beclin 1 via ultraviolet radiation resistance-associated gene (UVRAG) to activate autophagy[6]. In 2003, the expression of UVRAG responsible for situs inversus totalis was examined in a case of a patient with situs inversus totalis, colon cancer with
hepatic metastasis, and cholecystolithiasis. Researchers found that there was no expression of UVRAG mRNA of colon mucosa adjacent to the tumor, thus suggesting that low or no UVRAG gene expression was partially responsible for this case[7]. The whole chain of Beclin 1, Bif-1, and UVRAG is highly associated with autophagy. If Beclin 1 is expressed at a low level, UVRAG cannot act as a pathway for Bif-1 to bind to Beclin 1, and autophagy cannot be activated at a high level. Since low or no UVRAG expression is linked to colon cancer[7], a low level of autophagy might be one of the decisive factors of tumorigenesis. The effect of autophagy on genomic stability also shows the anti-tumorigenesis character of autophagy shown in Fig. 2[6]. Abhydrolase domain containing 5 (ABHD5) competes with CASP3 to bind with BECN1, so the loss of ABHD5 leads to large amounts of BECN1 being cleaved by CASP3 and thus decreased the level of autophagy, contributing to genomic information and tumorigenesis of colon cells tumorigenesis[8].
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Figure 2. Autophagy may inhibit the occurrence of genomic instability by slowing the damage repair
cycle in which stem cells are involved
(2) Antagonistic roles of autophagy and apoptosis in tumorigenesis
The reason that cancer cells can reproduce themselves at an abnormally fast rate without “dying” is the lack of apoptosis program in them. An increase in autophagy can further inhibit apoptosis of tumor cells[9], and failure in normal apoptosis promotes carcinogenesis[10]. Under hypoxia conditions, autophagy is induced in tumor-initiating cells (TICs) of CRC cultures to increase the self-renewal ability of TICs via PRKC/PKC-EZR (ezrin) pathway[11]. Decrease of autophagy can also be done by melatonin which is capable of decreasing the progression of
colon carcinogenesis[12]. In autophagy-inhibited cells, benign tumor growth is also
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inhibited due to the stress response induced by lack of autophagy[13], and stress response is one of the core reasons that induce apoptosis[14]. RACK1 is an oncogene that induces autophagy in intestinal epithelial cancerous cells, and its expression is progressively increased in the carcinogenesis process of intestinal epithelial cells (IECs)[15].
(3) Autophagy’s role in inflammation and CRC
Patients with inflammatory bowel diseases are at a higher danger of developing CRC[9]. If the role of autophagy in inflammation-related tumorigenesis is clearly figured out, autophagy genes or proteins might become a potential therapeutic target for CRC treatment. Autophagy plays dual roles in inflammation and tumor formation. On the one hand, autophagy helps to keep cell membrane integrity and prevents the accumulation of hazardous components, directly inhibits inflammation, and regulates the production of inflammatory factors[5], thereby reducing the risk of inflammation and tumorigenesis. Cadwell et al. found that Atg16L1 deficiency reduces the level of antimicrobial peptides, resulting in excessive accumulation of intestinal microbes, stimulating the production of IL-23 and IL-17, and ultimately leading to the development of CRC[5]. Colibactin-producing Escherichia coli (CoPEC), a bacteria associated with CRC, induces autophagy in IECs to activate the repairment of DNA damage, thus reducing the risk of inflammation-related colorectal carcinogenesis shown in Fig. 3[16]. Liu et al. reported that BRG1, a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7, and Wipi2 (genes responsible for autophagosome genesis), is closely linked to inflammation-associated CRC. Mice with deletion of BRG1 developed spontaneous colitis, whereas overexpression of BRG1 protected mice from colitis and CRC via mediating reactive oxygen species (ROS) and maintaining cell barrier integrity[17]. On the other hand, the accumulation of mitochondrial ROS promotes autophagy which acts as the second signal of inflammasome activation and pyroptosis, thus
leading to oncogenesis[18]. The activation of autophagy inhibits apoptosis of cancer cells, which is one of the leading causes of chemotherapy failures. Fusobacterium (F.) nucleatum is a gut biota that is abundant in CRC cells. When F. nucleatum targets TLR4 and MYD88 on CRC cells, it triggers the autophagy pathway via increasing the expression of ATG7 and ULK1[19]. In this case, autophagy acts protectively in cancer cells, yielding not ideal outcomes of chemotherapy treatments.
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Figure 3. Proposed model for the role of autophagy in colorectal carcinogenesis associated with
CoPEC colonization
3. Autophagy Promotes Tumor Growth and Metastasis
The uncontrolled proliferation process of CRC cells leads to hypoxia and starvation around the tumor, so autophagy occurs to degrade damaged cellular parts and assure the growth of the tumor. Therefore, autophagy serves as a protection mechanism for tumors, which means inhibiting protective autophagy might be a potential way to treat CRC. Failed apoptosis of CRC cells is closely linked to ch
emoresistance. Some genes, like groups of ATG4 genes, are responsible for regulating autophagy activity via controlling the role of LC3. The formation of an autolysosome involves lipidation of LC3-I so that it transforms to LC3-II to fuse the membranes of autophagosome and lysosome. LC3-I should be recycled through the process of delipidation to maintain a normal rate of autophagy, which means that the accumulation of not delipidated LC3-II causes attenuated autophagy[20]. S130 is a newly found molecule that can inhibit ATG4B with high selectivity; suppression of ATG4B activity decreases autophagy level via accumulating delipidated LC3-II [21]. 3-Methyladenine (3-MA) combined with hypoxia condition leads to an increase of apoptosis and a decrease in autophagy in CRC cells[22]. These studies reveal that autophagy might be a self-defense mechanism opposing apoptosis, so lack of autophagy makes CRC cells more vulnerable to chemotherapy drugs, improving the prognosis of CRC patients. Similarly, there are other ways to
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