lic pathway (43, 44), which may possibly play a role during VA therapy. Hence, it was recommended 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 significant influence on carcinogenesis and tumor biology (45), and it’s mostly metabolized to ornithine by arginase (46, 47). Arginine metabolism is viewed as to be a crucial regulator in controlling immune response (48, 49), inhibiting antitumor immune response (50, 51), and promoting tumor IL-10 Inhibitor list improvement (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 final results (Figures 7A ), we speculate that inhibiting arginineornithine metabolism can reduce ornithine content material, as a result decrease polyamine biosynthesis. Last but not least, our information revealed that high ODC1 expression was drastically linked with poor prognosis inFrontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Benefit MMAEBFCGDHFIGURE 7 | Elevated ODC1 expression is linked 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 significantly increased 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 individuals (Figures 7E ). In truth, ODC1 could be the exclusive gene encoding the rate-limiting enzyme with the polyamine biosynthesis pathway, which catalyzes ornithine to polyamines. Mounting research reported that ODC1 expression was elevated in several 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 via 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 cut down ODC1 to prolong the survival time of MM. On the other hand, more function is needed 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 CDC Inhibitor site decarboxylase (61), to improve the impact of MM remedy. In summary, our study demonstrates that mixture of acupuncture and bortezomib has synergistic effects inside 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 advantage MM patients.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 information, 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 to the report and