High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma

Zhigang Wang; Hongsai Chen; Lu Xue; Weiwei He; Wenying Shu; Hao Wu; Zhaoyan Wang

Translational Oncology (Aug 2021)

High throughput proteomic and metabolic profiling identified target correction of metabolic abnormalities as a novel therapeutic approach in head and neck paraganglioma

Zhigang Wang,
Hongsai Chen,
Lu Xue,
Weiwei He,
Wenying Shu,
Hao Wu,
Zhaoyan Wang

Affiliations

Zhigang Wang: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Hongsai Chen: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Lu Xue: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Weiwei He: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Wenying Shu: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
Hao Wu: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China.
Zhaoyan Wang: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China; Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China; Corresponding authors at: Department of Otolaryngology Head & Neck Surgery, The Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, No. 639, Zhi-Zao-Ju Road, Shanghai 200011, China.

Journal volume & issue: Vol. 14, no. 8
p. 101146

Abstract

Read online

Head and neck paragangliomas (HNPGLs) are rare neoplasms that represent difficult treatment paradigms in neurotology. Germline mutations in genes encoding succinate dehydrogenase (SDH) are the cause of nearly all familial HNPGLs. However, the molecular mechanisms underlying tumorigenesis remain unclear. Mutational analysis identified 6 out of 14 HNPGLs harboring clinicopathologic SDH gene mutations. The SDHB gene was most frequently mutated in these patients, and western blot showed loss of SDHB protein in tumors with SDHB mutations. The paraganglioma cell line (PGL-626) was established from a sample that harbored a missense SDHB mutation (c.649C > T). Spectrometric analysis using tandem mass tags identified 151 proteins significantly differentially expressed in HNPGLs compared with normal nerves. Bioinformatics analyses confirmed the high level of enrichment of oxidative phosphorylation and metabolism pathways in HNPGLs. The mitochondrial complex subunits NDUFA2, NDUFA10, and NDUFA4, showed the most significantly increased expression and were localized predominantly in the cytoplasm of PGL-626 cells. The mitochondrial complex I inhibitor metformin exerted dose-dependent inhibitory effects on PGL-626 cells via cooperative down-regulation of NDUFA2, 4, and 10, with a significant decrease in the levels of reactive oxygen species and mitochondrial membrane potential. Further metabolomic analysis of PGL-626 cells showed that metabolites involved in central carbon metabolism in cancer and sphingolipid signaling pathways, pantothenate and CoA biosynthesis, and tryptophan and carbon metabolism were significantly altered after metformin treatment. Thus, this study provides insights into the molecular mechanisms underlying HNPGL tumorigenesis and identifies target correction of metabolic abnormalities as a novel therapeutic approach for this disease.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

About the journal

Abstract

Keywords