lic pathway (43, 44), which may perhaps play a part in the course of VA treatment. Thus, 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 considerable effect on carcinogenesis and tumor biology (45), and it really is mainly metabolized to ornithine by arginase (46, 47). Arginine metabolism is regarded as to be a crucial 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 final results (Figures 7A ), we speculate that inhibiting arginineornithine metabolism can reduce ornithine content, hence reduce polyamine biosynthesis. Last but not least, our data revealed that higher ODC1 expression was substantially associated with poor prognosis inFrontiers in Oncology | frontiersin.orgNovember 2021 | Volume 11 | ArticleKe et al.Acupuncture and Bortezomib Advantage MMAEBFCGDHFIGURE 7 | Enhanced 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 patients was correlated with poor OS in TT2 cohort, and APEX phase III clinical trial by log-rank test. (G, H) The mRNA degree of ODC1 from NP, MGUS, SMM, and MM was substantially enhanced 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 ). The truth is, ODC1 will be the exclusive gene encoding the rate-limiting enzyme with the polyamine biosynthesis pathway, which catalyzes ornithine to polyamines. Mounting studies reported that ODC1 expression was KDM4 Inhibitor manufacturer improved in lots of cancers, like esophageal carcinoma (55), colorectal cancer (56), hepatocellular carcinoma (57), neuroblastoma (58), and ovarian cancer (59). LPAR1 Inhibitor Formulation Bianchi-Smiraglia A et al. (60) demonstrated that aryl hydrocarbon receptor (AHR) positively regulated intracellular polyamine production by way of 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 mixture of acupuncture and bortezomib can lower ornithine and lower ODC1 to prolong the survival time of MM. On the other hand, a lot more function is required to further validate the therapeutic impact of targeting arginine-ornithine metabolism and interfering ODC1 expression by using RNAi or difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase (61), to enhance the impact 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 via decreasing ornithine. Targeting ornithine-mediated metabolism may very well be a promising technique to advantage MM sufferers.ETHICS STATEMENTThe animal study was reviewed and authorized by the Institutional Ethics Overview 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 operate and analyzed the information. All authors contributed towards the post and