| Cancer is one of the leading causes of death worldwide. Studies now believe thatcancers are the results of the interaction between genetic factors like chromosomalimbalance and environmental factors including physical carcinogens, dietary factors,infections and environmental pollutants. These factors will promote accumulation ofmisfolded/unfolded proteins which will be eliminated through an endoplasmicreticulum-associated degradation pathway (ERAD) including ubiquitin/proteasomepathway (ERADI) and autophagic/lysosomal pathway (ERADII) in cells. However, ifthe stress is prolonged or the degradation pathway is blocked, cells will be damagedthrough programmed cell death that may contribute to the pathogenesis of many dieases,including cancers.Arsenic (As), known as an environmental heavy metal pollutant, has been classified as aclass I human carcinogen by the International Agency of Research on Cancer (IARC).Most human As exposure occurs from drinking contaminated water that containinginorganic As. Exposure to arsenic and its compounds, especially the trioxide (As2O3),promotes the development of many tumors. As2O3-induced tumor angiogenesis andoxidative stress, inhibition of DNA repair and disruption of genomic stability, areconsidered to be key factors of carcinogenesis. However, the exact molecularmechanisms of As2O3in promoting tumor development and the function of autophagyin it are still unclear. Autophagy is the major process involved in the lysosomal degradation of proteins andorganelles within cells and is activated in response to a whole host of stimuli, includinghypoxia, nutrient depletion, metabolic stress and environmental carcinogens. It is ahomeostatic process that takes place in all eukaryotic cells and involves thesequestration of cytoplasmic components in double membraned autophagosomes. Thenthe autophagosome fuses with the lysosome to become an autolysosome and degradethe materials within it.Autophagy influences a number of processes that have various effects on diseaseprogression. Autophagy has both promotion and suppression roles in cancer. For example,autophagy may function as a tumor suppressor by eliminating damaged protein andpreserving cellular homoeostasis. On the other hand，in established cancers, it may alsoprovide an energy source for tumor cells which can survive an environment that isunfavorable for normal cells. Many anti–cancer drugs are found to lead to cell deaththrough autophagic pathway. Since it exerts a multifactorial function on the initiationand progression of cancer, autophagy has become the hot topic of cancer researchaiming to understand the pathogenesis of cancers and find novel intervention loci.Theregulatory mechanism of autophagy is multilayered and complex. A latest researchsuggests that Small VCP/p97-interacting protein (SVIP) may play a regulatory role inautophagy, specifically, studies found SVIP is an endogenous inhibitor of ERAD.In this study, we first assessed the expression of SVIP in different tumor cell lines andfound that it varied in these cell lines. In addition, the level of SVIP in human colorectalcaner cell lines SW480cell lines is lower than in human colorectal caner metastatic sitecell lines SW620, which came from the same patient with SW480cells. Andknockdown of SVIP in SW620cells reduced the colony formation ability of cells.While overexpression of SVIP in SW480showed the same result. These findings indicate that appropriate level of SVIP is essential for the growth of cancer cells.We further treated cells with environmental carcinogen As2O3and found that bothprotein levels and mRNA levels of SVIP are increased in these two cell lines. We alsoanalyzed the levels of LC3and p62, which were frequently as markers of autophagy.We found that As2O3induced autophagy which could be blocked by BafilomycinA1(Baf-A1), a kind of autophagy inhitior, in cells. Starvation, a potent physiologicalinducer of autophagy, was used as a positive control in this study. Although autophagywas indeed induced by starvation in both cell lines, the levels of SVIP were decreased.Similarly, we also found that SVIP knockdown significantly reduced the levels of LC3in SW620cells, which was not abrogated in the presence of As2O3. These resultssuggest that the function of As2O3on induction of autophagy in cells is different fromstarvation, and SVIP may be the key regulator in this process.In addition, we also found that chronic low-dose As2O3treatment promotes colorectalcancer cells colony formation ability, proliferation and migration, which suggest thatchronic low-dose As2O3exposure is a promoting factor of tumor progression. Thesedata suggested that disturb the activation of autophagy may influence the colonyformation ability of tumor cells.Overall, our results show that chronic low-dose As2O3exposure may regulate the SVIPexpression, which in turn, may regulate the induction of autophagy activities and thegrowth of human colorectal cancer. |
PDF Full Text Request