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1、Introduction
Autophagy is a prevalent life phenomenon in eukaryotic cells, which is a metabolic process transfers transmutative, senescent or injured proteins and organelles to lysosomes and then degrades them. In eukaryotes, autophagy stabilizes intracellular stability by renewing functions such as proteins and organelles. (Yang, 2015)
Autophagy occurs rapidly when environmental stress such as starvation, lack of growth factors or increasing energetic requirements is encountered. Amino acids producing via autophagy can be used to resynthesize proteins to maintain ATP production in cells. It also has important functions of removing aggregated or damaged proteins and organelles and eliminating bacteria or viruses in infected cells. In the treatment of cancer, on the one hand, autophagy can prevent apoptosis induced by antitumor drugs and promote tumor resistance. On the other hand, the death of autophagic cells may be a way of death of tumor cells with apoptosis tolerance. Therefore, cell autophagy has a dual impact on tumor cell resistance. From the above aspects, autophagy has a broad research prospect for further study, which will be an imperative issue to be resolved.
2、The Basic Process of Autophagy
Autophagy is an important pathway for cellular lysosomes to degrade damaged organelles and misfolded proteins. Autophagy can be seperated with three genres according to the pathways that substrates entries into lysosomes: (1) Macroautophagy: Substance in the cytoplasm are transported into lysosomes through the formation of vesicles and used to degrade cellular organelles and proteins that are aged or damaged in the cells. “(2)Microautophagy: Cellular material is directly endocytosed and degraded by lysosomes. (3) Chaperone-mediated autophagy(CMA): Cells in the soluble protein are directly into the lysosome to be degraded through the chaperone.” (T.﹠D.J., 2005;K.﹠M.C., 2012)
Therefore, the following description mainly focuses on macrophage.In macrophage, cytoplasmic proteins and dysfunctional organelles are surrounded by a bilayer membrane structure that is not lysosome-derived and form autophagosome. Driven by the cytoskeleton, the outer membrane of autophagosome fuses with the lysosomal membrane. And the inner membrane and its entrapped substance enter the lysosomes, making them degranulate to release proteolytic enzymes and degrade autophagosome. Degraded products are necessary for cell survival and can be reused by cells. Part of degraded products are necessary for cell survival and can be reused by cells. 3、The Relationship between Autophagy and Tumorigenesis
In the process of tumorigenesis and development, the role of autophagy is bi-directional. On the one hand, autophagy can prevent the accumulation of toxic or carcinogenic proteins and inhibit the canceration of cells. On the other hand, autophagy can also enhance the ability of tumor to adapt so that cells survive under the circumstance of metabolic stress or immunosuppression, promoting tumor growth.
3.1. Autophagy on Tumor Inhibition
3.1.1. Autophagy Can Inhibit Tumor Development and Metastasis
When the metabolic pressure is large enough, the tumor cells can not maintain their own survival, which causes necrosis. And then necrosis often induces inflammatory reactions, leading to the infiltration of macrophage and the release of proinflammatory cytokines, which then promotes the growth of the tumor.
The autophagy can be improved by increasing the adaptability of tumor cells to metabolic stress, the inhibition of necrosis, the reduction of macrophage infiltration, the indirect inhibition of tumor development and the suppression of tumor growth. “And meanwhile, with the tumor immune response reducing, tumor growth and metastasis are inhibited.”(Su﹠Yang﹠Xu﹠Chen﹠Yu, 2015)
3.1.2. Overautophagy Can Cause Cell Death
The over-upregulation of autophagy can cause cell death, which is the type II programmed cell death. This cell form of death is different with biological characteristics of apoptosis, which manifests a large number of vacuolar structure packaging the cytoplasm and organelles, as well as the degradation of components within the vacuolesthe via lysosome. (Shi﹠Wang, 2011)
Autophagy can induce cell death when cells can no longer maintain their own survival.
3.2. Autophagy on The Promotion of Cancer
“Although normal autophagy has an inhibitory effect on the development of tumors, some tumor cells can use autophagy to fight against the stress environment and enhance the survival ability after the tumor is formed.” (Wu﹠Jiang﹠Ding﹠Shao﹠Liu, 2015) The rapid growth of tumors requires a lot of nutrition and oxygen. In the area of lacking tumor blood vessels, hypoxia may induce cellular anti-apoptosis, drugresistance, anti-radiation and metastatic potentialities.
Studies have shown that hypoxia inducible factor-1α (HIF-1α) is a key regulator of cell hypoxia stress response, which is highly expressed in hypoxic tumor cells. And at the same time, with the inducement of cell autophagy, HIF-1α can promote cell survival and inhibit apoptosis.Hypoxia is a crucial reason why tumor metabolism is inhibited. Autophagy assists tumor cells to cope with metabolic stress and enhances the ability of tumor cells to adapt to hypoxic environment through a variety of ways. 4、Summary and Outlook
Autophagy is an ubiquitous and important life phenomenon and is widely involved in a variety of physiological and pathological processes. At present, the treatment of cancer has entered the era of targeted therapy, and autophagy as a potential target for the treatment of cancer has also been studied as prevalent trend, drawing attention to many scientists. With the deepening of the research on the mechanism of autophagy, as well as the rapid development of various biotechnologies, the mechanism of autophagy in the occurrence and development of tumors will be also further explored. And it provides new ideas for the drug research of tumors, which opens up new prospects for the treatment of tumors and brings good blessing to human beings.
References:
[1] Huimei,Wu.,﹠Zifeng,Jiang.,﹠Peishan,Ding.,﹠Lijie,Shao.,﹠Rongyu,liu.(2015). Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Scientific Reports, 5, 12291.
[2] Susmita,K.,﹠Ana,M.C.(2012).Chaperone-mediated autophagy:a unique way to enter the lysosome world. Trends Cell Biol, 22, 8, 407-417.
[3] Yorimitsu,T.,﹠Klionsky,D.J.(2005). Autophagy:molecular machinery for self-eating. Cell Death Differ, 12, 1542-1552.
[4] Zhenyi,Su.,﹠Zuozhang,Yang.,﹠Yongqing,Xu.,﹠Yongbin,Chen.,﹠Qiang,Yu.(2015). Apoptosisi, autophagy, necroptosis, and cancer metastasis. Molecular Cancer, 14, 48.
[5] 石峰,王明榮.细胞自噬及其与肿瘤关系的研究进展[J].中国细胞生物学学报,2011,33(12):1366-1373.
[6] 杨晨,李萍,梁廷明.细胞自噬与肿瘤的关系研究进展[J].生命科学,2015,02(27):151-160.
Autophagy is a prevalent life phenomenon in eukaryotic cells, which is a metabolic process transfers transmutative, senescent or injured proteins and organelles to lysosomes and then degrades them. In eukaryotes, autophagy stabilizes intracellular stability by renewing functions such as proteins and organelles. (Yang, 2015)
Autophagy occurs rapidly when environmental stress such as starvation, lack of growth factors or increasing energetic requirements is encountered. Amino acids producing via autophagy can be used to resynthesize proteins to maintain ATP production in cells. It also has important functions of removing aggregated or damaged proteins and organelles and eliminating bacteria or viruses in infected cells. In the treatment of cancer, on the one hand, autophagy can prevent apoptosis induced by antitumor drugs and promote tumor resistance. On the other hand, the death of autophagic cells may be a way of death of tumor cells with apoptosis tolerance. Therefore, cell autophagy has a dual impact on tumor cell resistance. From the above aspects, autophagy has a broad research prospect for further study, which will be an imperative issue to be resolved.
2、The Basic Process of Autophagy
Autophagy is an important pathway for cellular lysosomes to degrade damaged organelles and misfolded proteins. Autophagy can be seperated with three genres according to the pathways that substrates entries into lysosomes: (1) Macroautophagy: Substance in the cytoplasm are transported into lysosomes through the formation of vesicles and used to degrade cellular organelles and proteins that are aged or damaged in the cells. “(2)Microautophagy: Cellular material is directly endocytosed and degraded by lysosomes. (3) Chaperone-mediated autophagy(CMA): Cells in the soluble protein are directly into the lysosome to be degraded through the chaperone.” (T.﹠D.J., 2005;K.﹠M.C., 2012)
Therefore, the following description mainly focuses on macrophage.In macrophage, cytoplasmic proteins and dysfunctional organelles are surrounded by a bilayer membrane structure that is not lysosome-derived and form autophagosome. Driven by the cytoskeleton, the outer membrane of autophagosome fuses with the lysosomal membrane. And the inner membrane and its entrapped substance enter the lysosomes, making them degranulate to release proteolytic enzymes and degrade autophagosome. Degraded products are necessary for cell survival and can be reused by cells. Part of degraded products are necessary for cell survival and can be reused by cells. 3、The Relationship between Autophagy and Tumorigenesis
In the process of tumorigenesis and development, the role of autophagy is bi-directional. On the one hand, autophagy can prevent the accumulation of toxic or carcinogenic proteins and inhibit the canceration of cells. On the other hand, autophagy can also enhance the ability of tumor to adapt so that cells survive under the circumstance of metabolic stress or immunosuppression, promoting tumor growth.
3.1. Autophagy on Tumor Inhibition
3.1.1. Autophagy Can Inhibit Tumor Development and Metastasis
When the metabolic pressure is large enough, the tumor cells can not maintain their own survival, which causes necrosis. And then necrosis often induces inflammatory reactions, leading to the infiltration of macrophage and the release of proinflammatory cytokines, which then promotes the growth of the tumor.
The autophagy can be improved by increasing the adaptability of tumor cells to metabolic stress, the inhibition of necrosis, the reduction of macrophage infiltration, the indirect inhibition of tumor development and the suppression of tumor growth. “And meanwhile, with the tumor immune response reducing, tumor growth and metastasis are inhibited.”(Su﹠Yang﹠Xu﹠Chen﹠Yu, 2015)
3.1.2. Overautophagy Can Cause Cell Death
The over-upregulation of autophagy can cause cell death, which is the type II programmed cell death. This cell form of death is different with biological characteristics of apoptosis, which manifests a large number of vacuolar structure packaging the cytoplasm and organelles, as well as the degradation of components within the vacuolesthe via lysosome. (Shi﹠Wang, 2011)
Autophagy can induce cell death when cells can no longer maintain their own survival.
3.2. Autophagy on The Promotion of Cancer
“Although normal autophagy has an inhibitory effect on the development of tumors, some tumor cells can use autophagy to fight against the stress environment and enhance the survival ability after the tumor is formed.” (Wu﹠Jiang﹠Ding﹠Shao﹠Liu, 2015) The rapid growth of tumors requires a lot of nutrition and oxygen. In the area of lacking tumor blood vessels, hypoxia may induce cellular anti-apoptosis, drugresistance, anti-radiation and metastatic potentialities.
Studies have shown that hypoxia inducible factor-1α (HIF-1α) is a key regulator of cell hypoxia stress response, which is highly expressed in hypoxic tumor cells. And at the same time, with the inducement of cell autophagy, HIF-1α can promote cell survival and inhibit apoptosis.Hypoxia is a crucial reason why tumor metabolism is inhibited. Autophagy assists tumor cells to cope with metabolic stress and enhances the ability of tumor cells to adapt to hypoxic environment through a variety of ways. 4、Summary and Outlook
Autophagy is an ubiquitous and important life phenomenon and is widely involved in a variety of physiological and pathological processes. At present, the treatment of cancer has entered the era of targeted therapy, and autophagy as a potential target for the treatment of cancer has also been studied as prevalent trend, drawing attention to many scientists. With the deepening of the research on the mechanism of autophagy, as well as the rapid development of various biotechnologies, the mechanism of autophagy in the occurrence and development of tumors will be also further explored. And it provides new ideas for the drug research of tumors, which opens up new prospects for the treatment of tumors and brings good blessing to human beings.
References:
[1] Huimei,Wu.,﹠Zifeng,Jiang.,﹠Peishan,Ding.,﹠Lijie,Shao.,﹠Rongyu,liu.(2015). Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Scientific Reports, 5, 12291.
[2] Susmita,K.,﹠Ana,M.C.(2012).Chaperone-mediated autophagy:a unique way to enter the lysosome world. Trends Cell Biol, 22, 8, 407-417.
[3] Yorimitsu,T.,﹠Klionsky,D.J.(2005). Autophagy:molecular machinery for self-eating. Cell Death Differ, 12, 1542-1552.
[4] Zhenyi,Su.,﹠Zuozhang,Yang.,﹠Yongqing,Xu.,﹠Yongbin,Chen.,﹠Qiang,Yu.(2015). Apoptosisi, autophagy, necroptosis, and cancer metastasis. Molecular Cancer, 14, 48.
[5] 石峰,王明榮.细胞自噬及其与肿瘤关系的研究进展[J].中国细胞生物学学报,2011,33(12):1366-1373.
[6] 杨晨,李萍,梁廷明.细胞自噬与肿瘤的关系研究进展[J].生命科学,2015,02(27):151-160.