lic pathway (43, 44), which could play a function in the course of VA therapy. Hence, it was suggested that ornithine may be a promising biomarker of VA therapy for MM (Figures 6A ). Arginine serving as a semi-essential amino acid possesses a important impact on carcinogenesis and tumor biology (45), and it is mainly metabolized to ornithine by arginase (46, 47). Arginine metabolism is deemed to be an essential 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 make putrescine, that 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, therefore reduce polyamine biosynthesis. Final but not least, our information revealed that high ODC1 expression was substantially linked with poor prognosis GSK-3 Inhibitor Storage & Stability inFrontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Advantage MMAEBFCGDHFIGURE 7 | Improved ODC1 expression is connected 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 enhanced in MM samples by ordinary one-way ANOVA test.Frontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Benefit MMMM sufferers (Figures 7E ). Actually, ODC1 may be the exclusive gene encoding the rate-limiting enzyme in the polyamine biosynthesis pathway, which catalyzes ornithine to polyamines. Mounting research reported that ODC1 expression was elevated in quite a few cancers, for example 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 through direct transcriptional activation of ODC1 and AZIN1 genes, which inhibited the aryl hydrocarbon receptor/polyamine biosynthesis axis to suppress MM progression. Taken collectively, it might be concluded that mixture of acupuncture and bortezomib can decrease ornithine and CA XII Inhibitor custom synthesis lessen ODC1 to prolong the survival time of MM. On the other hand, additional operate is required 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 impact of MM treatment. In summary, our study demonstrates that combination of acupuncture and bortezomib has synergistic effects inside the therapy of MM, which prolongs survival time of MM mice by way of decreasing ornithine. Targeting ornithine-mediated metabolism could possibly be a promising approach to advantage MM patients.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 made 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 function and analyzed the information. All authors contributed towards the write-up and