lic pathway (43, 44), which could play a function through VA treatment. For that reason, it was recommended that ornithine may well be a promising biomarker of VA therapy for MM (Figures 6A ). Arginine serving as a semi-essential amino acid possesses a substantial impact on carcinogenesis and tumor biology (45), and it truly is largely metabolized to ornithine by arginase (46, 47). Arginine metabolism is thought of to become a vital regulator in controlling immune response (48, 49), inhibiting antitumor immune response (50, 51), and advertising tumor development (34, 52). Ornithine is decarboxylated by ODC1 to generate putrescine, which is the rate-limiting step in polyamine biosynthesis (53, 54). Combined with cellular proliferation outcomes (Figures 7A ), we speculate that inhibiting arginineornithine metabolism can minimize ornithine content material, as a result lower polyamine biosynthesis. Final but not least, our data revealed that high ODC1 expression was considerably associated with poor prognosis inFrontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Advantage MMAEBFCGDHFIGURE 7 | Improved ODC1 expression is associated 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 sufferers was correlated with poor OS in TT2 cohort, and APEX phase III clinical trial by log-rank test. (G, H) The mRNA level of ODC1 from NP, MGUS, SMM, and MM was significantly 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 individuals (Figures 7E ). In reality, ODC1 is definitely the exclusive gene encoding the rate-limiting enzyme in the polyamine biosynthesis pathway, which catalyzes ornithine to Kainate Receptor Agonist list polyamines. Mounting studies reported that ODC1 expression was enhanced in a lot of cancers, which include esophageal carcinoma (55), colorectal cancer (56), hepatocellular carcinoma (57), neuroblastoma (58), and ovarian cancer (59). Bianchi-Smiraglia A et al. (60) demonstrated that aryl IL-10 Inducer Storage & Stability hydrocarbon receptor (AHR) positively regulated intracellular polyamine production through direct transcriptional activation of ODC1 and AZIN1 genes, which inhibited the aryl hydrocarbon receptor/polyamine biosynthesis axis to suppress MM progression. Taken with each other, it may be concluded that mixture of acupuncture and bortezomib can lower ornithine and lower ODC1 to prolong the survival time of MM. However, more function is necessary to further validate the therapeutic effect of targeting arginine-ornithine metabolism and interfering ODC1 expression by using RNAi or difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase (61), to improve the impact of MM remedy. In summary, our study demonstrates that combination 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 can be a promising method to benefit MM sufferers.ETHICS STATEMENTThe animal study was reviewed and approved by the Institutional Ethics Assessment Boards of Nanjing University of Chinese Medicine.AUTHOR CONTRIBUTIONSYY, CG, and BX created 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 operate and analyzed the data. All authors contributed to the article and