ABSTRACT
Ovarian cancer is the deadliest gynecologic cancer worldwide, and the therapeutic options are limited. PARP inhibitor (PARPi) represents an effective therapeutic strategy and has been approved for maintenance therapy. However, the intrinsic or acquired resistance to PARPi becomes a big challenge. To investigate the mechanisms for PARPi resistance, we analysed public databases and established Olaparib-resistant ovarian cancer cells for exploration. Our results showed that the inflammatory pathway and adenosine receptor A2b (Adora2b/A2B ) expression were significantly increased in Olaparib-resistant cells. A2B was highly expressed in recurrent ovarian tumours and negatively correlated with the clinical outcomes in cancer patients. Olaparib treatment enhanced A2B expression through NF-κB activation. The elevated A2B contributed to Olaparib resistance by sensing adenosine signal and promoting tumour cell survival, growth and migration via IL-6-STAT3 signalling. Therefore, inhibition of A2B -IL-6-STAT3 axis could overcome Olaparib resistance and synergize with Olaparib to reduce cancer cell growth and lead to cell death. Our findings reveal a critical role of A2B signalling in mediating PARPi resistance independent of DNA damage repair, providing insights into developing novel therapies in ovarian cancers.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Humans , Female , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Interleukin-6/genetics , Interleukin-6/metabolism , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Antineoplastic Agents/pharmacology , Receptors, Purinergic P1/metabolism , Phthalazines/pharmacology , Phthalazines/therapeutic use , Cell Line, Tumor , STAT3 Transcription Factor/metabolismABSTRACT
Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.
Subject(s)
Genome-Wide Association Study , Longevity/genetics , Apolipoproteins E/genetics , Asian People/genetics , China , Gene Regulatory Networks , Genetic Loci , Humans , Membrane Transport Proteins/genetics , Mitochondrial Precursor Protein Import Complex Proteins , Polymorphism, Single Nucleotide , Principal Component AnalysisABSTRACT
OBJECTIVE: We isolated 339 bacillus strains from 72 soil samples all over the country, then purified their antimicrobial compounds and studied the antibacterial activity, to enrich bacillus resources and explore their second metabolites. METHODS: A bacillus strain with strong antibacterial activity was selected by dilution plate and water bath heating from a soil sample from a peanut plantation in Henan Province; this strain was identified according to morphological observation, physiological and biochemical characteristics, and consequences of 16S rRNA homologous analysis. Antibacterial compound from the identified strain, Bacillus amyloliquefaciens X030, was separated and purified by acetone precipitation, Sephadex chromatography, C18 reverse phase column chromatography. Its molecular weight was analyzed by LC-MS/MS. The antibacterial activity was characterized by disc diffusion and plate two-way cultivation. RESULTS: Bacillus amyloliquefaciens was isolated that not only has antibacterial activity against Staphylococcus aureus, Candida albican and Saccharomycetes; but also against Pyriculariaoryzae, Chili pointed cell anthrax, Gloeosporium eriobotryae speg and Phytophthora parasitica. The compound was confirmed as polypeptide. CONCLUSION: Bacillus amyloliquefaciens X030 can produce a polypeptide that inhibits pathogenic bacteria and plant pathogenic fungi.
