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  • bromodomain Discussion It is widely known that wild type p

    2018-10-25

    Discussion It is widely known that wild-type p53 protein is a tumor suppressor, whereas mutant p53 proteins can actively contribute to tumorigenesis. p53 mutations have been revealed to be present in numerous human tumors (Muller and Vousden, 2013). Recently, Freed-Pastor et al. reported the significant upregulation of mutant p53 in the mevalonate pathway. Specifically, mutant p53 is recruited to sterol gene promoters partly via SREBP transcription factors and induces sterol biosynthesis of genes that increase the malignancy of breast cancers. Inhibition of mevalonate pathway by statins is sufficient to block the phenotypic effects of mutant p53 on breast tissue architecture. This study demonstrated a novel anti-tumor mechanism in which statins prevent the tumor progression by blocking the signaling pathway of mutant p53 (Freed-Pastor et al., 2012). In our study, we demonstrate the role of statins on normal, wild-type p53. Specifically, we illustrate that fluvastatin induces nuclear wild-type p53 expression activating the AMPK-mTOR-dependent autophagy in cancer bromodomain to increase anti-bone metastatic effect. This suggests that statins can regulate both normal p53 and mutant p53 functions and contribute to a tumor suppressive effect. Pei-Ming Yang et al. reported that atorvastatin could inhibit the growth of hepatocellular carcinoma and colorectal carcinoma cells via induction of apoptosis; inhibition of autophagy increased atorvastatin-induced cell apoptosis (Yang et al., 2010). Unlike this study looking at in vitro cell apoptosis in primary cancer cell lines, our study focuses on autophagy in bone metastasis. In fact, the role of autophagy in cancer metastasis is quite complicated (Kenific et al., 2010). Generally, induction of autophagy could either promote the tumor progression or suppression and is mostly dependent on cancer stages, cancer types and tumor microenvironment. Autophagy may exert a suppressive effect in the early stage of cancer metastasis by promoting oncogene-induced senescence, restricting tumor necrosis or inflammation and triggering autophagic cell death to reduce invasion and dissemination of cancer cells from the primary site. In addition, autophagy was reported to degrade TWIST1 to restrict epithelial-mesenchymal transition (Qiang and He, 2014). During advanced cancer stages, autophagy may accelerate metastasis by supporting extracellular matrix (ECM)-detached metastatic cell survival and inducing metastatic cells to enter dormancy if they fail to establish a contact with the ECM in the new environment. Furthermore, tumor colonization at a distant site is possible by increasing the motility of tumor cell via autophagy-induced degradation of paxillin and focal adhesion turnover (Su et al., 2015a; Peng et al., 2013; Sharifi et al., 2016). Recently, Rosenfeldt et al. reported that p53 status in tumor host determined the role of autophagy in bromodomain pancreatic tumor development (Rosenfeldt et al., 2013). Taken together, these studies imply that the role of autophagy in tumorigenesis and progression is highly variable and correlated with timing, space and tumor microenvironment. Induction of autophagy in cancer cells may serve an anti-cancer role by enhancing immunosurveillance. For example, in response to chemotherapeutic drugs, autophagy-competent tumors release the chromatin binding protein high mobility group B1 (HMGB1), calreticulin and adenosine triphosphate (ATP) that attract dendritic cells and T lymphocytes into the tumor microenvironment and promote anti-cancer responses (Michaud et al., 2011; Apetoh et al., 2007). In this study, we reveal that induction of autophagy by fluvastatin restricted the SPC-A-1 cells metastasis in nude mice; enhanced level of autophagy in cancer cells can attenuate the metastatic ability independent of adaptive immunity activation. Although we cannot exclude the possibility that autophagy-related innate immune responses are involved in clearance of SPC-A-1 cells, in-vitro experiments reveal that induction of autophagy by fluvastatin in these lung cancer cells greatly lowered their migratory and invasive ability without affecting the proliferation property. Therefore, induction of autophagy may serve an anti-cancer function in an immune-dependent or -independent way.