Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.
Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.
复制标题
DOI：
10.1002/jbmr.4532
复制
发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
内生软骨瘤和软骨肉瘤是常见的软骨肿瘤，分别为良性或恶性。这些肿瘤中的大多数在IDH 1或IDH 2中具有突变。谷氨酰胺代谢被认为是IDH突变肿瘤的关键调节因子。使用遗传学和药理学方法，我们证明了谷氨酰胺酶介导的谷氨酰胺代谢在具有IDH 1或IDH 2突变的内生软骨瘤和软骨肉瘤中起着不同的作用。谷氨酰胺通过不同的下游代谢产物影响这些肿瘤中细胞的分化和活力。在小鼠内生软骨瘤样病变发展过程中，谷氨酰胺衍生的α-酮戊二酸促进肥大软骨细胞分化并调节软骨细胞增殖。Idh 1突变的软骨细胞中转氨酶的缺失增加了内生软骨瘤样病变的数量和大小。相比之下，软骨肉瘤异种移植物中转氨酶的药理学抑制部分降低了总体肿瘤负荷，因为谷氨酰胺衍生的非必需氨基酸在预防细胞凋亡中发挥了重要作用。这项研究表明，谷氨酰胺代谢在肿瘤发生和癌症维持中起着不同的作用。补充α-酮戊二酸和抑制GLS可能分别提供抑制内生软骨瘤和软骨肉瘤肿瘤生长的治疗方法。版权所有© 2022作者。《骨与矿物质研究杂志》由Wiley Periodicals LLC代表美国骨与矿物质研究学会（ASBMR）出版。
Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase‐mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma‐like lesion development, glutamine‐derived α‐ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma‐like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine‐derived non‐essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α‐ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
登录
查看更多内容
影响因子：
3
作者：
Mingote S;Masson J;Gellman C;Thomsen GM;Lin CS;Merker RJ;Gaisler-Salomon I;Wang Y;Ernst R;Hen R;Rayport S
通讯作者：
Rayport S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
2.6
作者：
Emadi, Ashkan;Ju, Sung Ah;Dang, Chi V.
通讯作者：
Dang, Chi V.