lic pathway (43, 44), which could play a role during VA remedy. Hence, it was suggested that ornithine may possibly be a promising biomarker of VA therapy for MM (Figures 6A ). Arginine serving as a semi-essential amino acid possesses a important influence on carcinogenesis and tumor biology (45), and it can be mainly metabolized to ornithine by arginase (46, 47). Arginine metabolism is viewed as to be an essential regulator in controlling immune response (48, 49), inhibiting antitumor immune response (50, 51), and promoting tumor development (34, 52). Ornithine is decarboxylated by ODC1 to make putrescine, that is the rate-limiting step in polyamine biosynthesis (53, 54). Combined with cellular Caspase Activator manufacturer proliferation outcomes (Figures 7A ), we speculate that inhibiting arginineornithine metabolism can lower ornithine content, hence lower polyamine biosynthesis. Final but not least, our information revealed that high ODC1 expression was significantly connected with poor prognosis inFrontiers in Oncology | Caspase 2 Activator supplier frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Advantage MMAEBFCGDHFIGURE 7 | Enhanced ODC1 expression is related with poor prognosis in MM. (A ) Arginine and its metabolite promoted ARP1, H929, OCI, and 5TMM3VT cell proliferation. P 0.05. (E, F) Higher ODC1 expression in MM individuals was correlated with poor OS in TT2 cohort, and APEX phase III clinical trial by log-rank test. (G, H) The mRNA amount of ODC1 from NP, MGUS, SMM, and MM was considerably improved in MM samples by ordinary one-way ANOVA test.Frontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Advantage MMMM patients (Figures 7E ). In actual fact, ODC1 may be the exclusive gene encoding the rate-limiting enzyme in the polyamine biosynthesis pathway, which catalyzes ornithine to polyamines. Mounting studies reported that ODC1 expression was elevated in several cancers, like esophageal carcinoma (55), colorectal cancer (56), hepatocellular carcinoma (57), neuroblastoma (58), and ovarian cancer (59). Bianchi-Smiraglia A et al. (60) demonstrated that aryl hydrocarbon receptor (AHR) positively regulated intracellular polyamine production via direct transcriptional activation of ODC1 and AZIN1 genes, which inhibited the aryl hydrocarbon receptor/polyamine biosynthesis axis to suppress MM progression. Taken together, it might be concluded that combination of acupuncture and bortezomib can decrease ornithine and decrease ODC1 to prolong the survival time of MM. Nonetheless, a lot more function is necessary to further validate the therapeutic impact of targeting arginine-ornithine metabolism and interfering ODC1 expression by utilizing RNAi or difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase (61), to enhance the effect of MM remedy. In summary, our study demonstrates that mixture of acupuncture and bortezomib has synergistic effects in the therapy of MM, which prolongs survival time of MM mice by means of decreasing ornithine. Targeting ornithine-mediated metabolism could be a promising approach to benefit MM sufferers.ETHICS STATEMENTThe animal study was reviewed and approved by the Institutional Ethics Critique Boards of Nanjing University of Chinese Medicine.AUTHOR CONTRIBUTIONSYY, CG, and BX designed the project, analyzed the data, and edited the manuscript. MK and JQ drafted the manuscript. MK, JQ, FH, XYL, HW, and XL performed the experimental work and analyzed the data. All authors contributed to the post and
