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Proto-Oncogene and Onco-Suppressor Gene Expression
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Stimulation of nonhematic cells by mitogenic agents may also be associated with alterations in protooncogene expression. The deazaguanine-derivative queuine behaves as a growth factor for HeLa cells and its action is accompanied by increased expression of the c-fos and c-myc genes.486 Stimulation of monkey kidney epithelial cells (BSC-1 cell line) with ADP, which is the most potent mitogen described for these cells, results in activation of c-H-ras and c-myc gene expression before the initiation of DNA synthesis.487 Proto-oncogene responses may exhibit variation among different types of mitogen-stimulated cells, as demonstrated with the use of specific inhibitors. Inhibitors of the nuclear enzyme ADP-ribosyltransferase (ADPRT) block differentiation of several eukaryotic cells, including an early event in lymphocyte activation. In PHA-stimulated human lymphocytes, ADPRT inhibition completely blocks the proliferative response and the increase in c-myc gene expression without affecting c-fos significantly.488 Conversely, in fibroblasts the serum-induced growth is not affected by ADPRT inhibitor, and both genes, c-myc and c-fos, are superinduced. Hence, there are differences between the responses of lymphocytes and fibroblasts to mitogenic stimulation, and also between the modes of regulation of c-fos and c-myc expression. A given proto-oncogene may serve different functions in different types of cells.
Obesity enriches for tumor protective microbial metabolites and treatment refractory cells to confer therapy resistance in PDAC
Published in Gut Microbes, 2022
Kousik Kesh, Roberto Mendez, Beatriz Mateo-Victoriano, Vanessa T Garrido, Brittany Durden, Vineet K Gupta, Alfredo Oliveras Reyes, Nipun Merchant, Jashodeep Datta, Santanu Banerjee, Sulagna Banerjee
In the gut, the microbiome, its metabolites are in a constant state of flux with the host tissue and its secretome. Several microbial metabolites like SCFAs, trimethylamine and polyamines have been directly implicated in driving tumorigenesis by contributing to protein and nucleotide synthesis for the rapidly proliferating tumor cells. Several studies show an enrichment of bacterial species that metabolize antioxidants and thus contribute to therapy resistance in multiple cancers.13,33,34 In this study, we observed that in obese animals, pancreatic tumors did not respond to standard of care treatments like Gemcitabine/Paclitaxel cocktail. Interestingly, when the microbial composition of the lean and the obese animals was changed by FMT, the obese mice started responding to therapy. A deeper analysis of the microbiome revealed an enrichment of bacteria secreting the bacterial metabolite queuosine (Q) in the obese animals and an enrichment of SAM secreting bacteria in the lean animals (Figure 3). Originally identified in E. coli, queuosine, Q was found to occupy the first anticodon position of tRNAs for histidine, aspartic acid, asparagine and tyrosine.35 The hyper-modified nucleobase of queuosine is queuine. In mammalian cells, queuine treatment is reported to modulate tolerance to hypoxia,36 influence proliferation37,38 and the expression of lactate dehydrogenase39 . Interestingly, we observe that bacterial taxa A. muciniphilia to be slightly enriched in pre-Q biosynthesis pathway in lean mice as well as in queuosine biosynthesis in obese mice (Figure 3b). Pre-Q can be utilized for synthesis of archeosine, tocoyamycin as well as queuosine in bacteria. It is possible that in lean mice, Pre-Q is not completely metabolized to Q, resulting in their sensitivity to the chemotherapeutic compounds.