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Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.

Simple Summary: Lung cancer remains the most commonly diagnosed cancer in the United States, only behind sex-specific cancers such as breast and prostate cancer. While not a sex-specific cancer, lung cancer exhibits sex-specific trends. Males are generally at a higher lifetime risk of developing lung cancer and have a higher mortality than females. There are also differences in therapeutic response between the sexes. As lung cancer is a complex disease, this difference is likely a combination of environmental factors, such as environmental exposures, diet, and smoking status, with inherent biological differences, such as the contribution of sex hormones and differences in immune responses. This narrative review focuses specifically on these biological differences and their contributions to this difference. Gaining a better understanding of the biological reasons behind this sex difference could lead to better treatment and screening decisions in the clinic that take the biological sex of the patient into consideration. Sex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes. [ABSTRACT FROM AUTHOR]

A screen for Saccharomyces cerevisiae temperature-sensitive silencing mutants identified a strain with a point mutation in the SIR2 gene. The mutation changed Ser276 to Cys. This amino acid is in the highly conserved [NAD.sup.+] binding pocket of the Sir2 family of proteins. Haploid strains of either mating type carrying the mutation were severely defective at mating at 37[degrees] but normal at 25[degrees]. Measurements of RNA from the HMR locus demonstrated that silencing was lost rapidly upon shifting the mutant from the low to the high temperature, but it took >8 hours to reestablish silencing after a shift back to 25[degrees]. Silencing at the rDNA locus was also temperature sensitive. On the other hand, telomeric silencing was totally defective at both temperatures. Enzymatic activity of the recombinant wild-type and mutant Sir2 protein was compared by three different assays. The mutant exhibited less deacetylase activity than the wild-type protein at both 37[degrees] and 25[degrees]. Interestingly, the mutant had much more [NAD.sup.+]- nicotinamide exchange activity than wild type, as did a mutation in the same region of the protein in the Sir2 homolog, Hst2. Thus, mutations in this region of the [NAD.sup.+] binding pocket of the protein are able to carry out cleavage of [NAD.sup.+] to nicotinamide but are defective at the subsequent deacetylation step of the reaction.

Research has been conducted on the nicotineamide-adenine dinucleotide (NAD)-dependent protein deacetylases from the SIR2 protein family. The determination of the crystal structures of the SIR2 homolog from Archaeglobus fulgidus complexed with NAD has been carried out and the results indicate that the protein has a domain with the Rossmann fold and a smaller domain with the three-stranded zinc ribbon motif.