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Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages

최연경|Lee Jaebon|Yun Jae Won|윤길숙|이유림|박수영|강유나|Jin Jonghwa|Byun Jun-Kyu|Park Keun-Gyu|Kim Dong-Ho|Park Mihyang|Kim Daehoon
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 1123-1136|DOI 10.1038/s12276-024-01214-1

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초록

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

Abstract

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

참고문헌 (53)

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관련 논문AI추천

Arginine Metabolism in Cancer Biology and ImmunotherapyDingYuan Bai, Guo Cheng, Jing LingJie, QuanJun Yang, Zhou YuXuan대한면역학회 · Immune Network2025 · 제25권 제4호The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages최동욱, Doyoung Park, Gyumin Lim, Hyon-Seung Yi, Sung-Jin Yoon생화학분자생물학회 · BMB Reports2022 · 제55권 제11호Targeting glutamine metabolism as a therapeutic strategy for cancer최연경, Byun Jun-Kyu, Jin Jonghwa, Park Keun-Gyu생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy임선아생화학분자생물학회 · BMB Reports2024 · 제57권 제9호Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?Huang Cheng, Li Jun, Luan Jiajie, Zhou Dexi거트앤리버 소화기연관학회협의회 · Gut and Liver2021 · 제15권 제4호Metabolic influence on macrophage polarization and pathogenesis이근욱, Bikash Thapa생화학분자생물학회 · BMB Reports2019 · 제52권 제6호

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