ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system

被引:95
作者
Zhang, Xiaoxin [1 ]
Dong, Yingchun [2 ]
Zhao, Mengxiang [3 ]
Ding, Liang [1 ]
Yang, Xihu [3 ]
Jing, Yue [1 ]
Song, Yuxian [1 ]
Chen, Sheng [4 ]
Hu, Qingang [1 ,3 ]
Ni, Yanhong [1 ]
机构
[1] Nanjing Univ, Nanjing Stomatol Hosp, Cent Lab, Med Sch, 30 Zhongyang Rd, Nanjing 210008, Peoples R China
[2] Nanjing Univ, Nanjing Stomatol Hosp, Med Sch, Dept Anesthesiol, Nanjing 210008, Peoples R China
[3] Nanjing Univ, Nanjing Stomatol Hosp, Med Sch, Dept Oral & Maxillofacial Surg, 30 Zhongyang Rd, Nanjing 210008, Peoples R China
[4] Nanjing Univ, Nanjing Stomatol Hosp, Med Sch, Dept Oral Pathol, Nanjing 210008, Peoples R China
来源
THERANOSTICS | 2020年 / 10卷 / 26期
基金
中国国家自然科学基金;
关键词
oral squamous cell carcinoma; cancer associated fibroblasts; ITGB2; lactate; NADH; oxidative phosphorylation system; CANCER-ASSOCIATED FIBROBLASTS; LACTATE METABOLISM; COMPLEX I; GLYCOLYSIS; CD18;
D O I
10.7150/thno.47901
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Objectives: Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that integrin beta 2 (ITGB2) is important for host defense, its expression profile and role in tumors, especially in cancer associated fibroblasts (CAFs) are still unknown. Methods: Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the ITGB2 expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare ITGB2 expression in normal fibroblasts (NFs) and cancer associated fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of ITGB2 expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of ITGB2 expressing CAFs in multiple in vitro and in vivo assays. Results: We found that CAFs exhibited significantly higher ITGB2 expression than the matched NFs. In addition, higher ITGB2 expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that ITGB2-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically, ITGB2 regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from ITGB2-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the ITGB2-expressing CAFs medium. Conclusions: Our study uncovered the ITGB2high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.
引用
收藏
页码:12044 / 12059
页数:16
相关论文
共 38 条
[1]   Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies [J].
Apicella, Maria ;
Giannoni, Elisa ;
Fiore, Stephany ;
Ferrari, Karin Johanna ;
Fernandez-Perez, Daniel ;
Isella, Claudio ;
Granchi, Carlotta ;
Minutolo, Filippo ;
Sottile, Antonino ;
Comoglio, Paolo Maria ;
Medico, Enzo ;
Pietrantonio, Filippo ;
Volante, Marco ;
Pasini, Diego ;
Chiarugi, Paola ;
Giordano, Silvia ;
Corso, Simona .
CELL METABOLISM, 2018, 28 (06) :848-+
[2]   Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer [J].
Ata, Rehman ;
Antonescu, Costin N. .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2017, 18 (01)
[3]   Metformin as a Tool to Target Aging [J].
Barzilai, Nir ;
Crandall, Jill P. ;
Kritchevsky, Stephen B. ;
Espeland, Mark A. .
CELL METABOLISM, 2016, 23 (06) :1060-1065
[4]   The reverse Warburg effect Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts [J].
Bonuccelli, Gloria ;
Whitaker-Menezes, Diana ;
Castello-Cros, Remedios ;
Pavlides, Stephanos ;
Pestell, Richard G. ;
Fatatis, Alessandro ;
Witkiewicz, Agnieszka K. ;
Vander Heiden, Matthew G. ;
Migneco, Gemma ;
Chiavarina, Barbara ;
Frank, Philippe G. ;
Capozza, Franco ;
Flomenberg, Neal ;
Martinez-Outschoorn, Ubaldo E. ;
Sotgia, Federica ;
Lisanti, Michael P. .
CELL CYCLE, 2010, 9 (10) :1960-1971
[5]   The Science and Translation of Lactate Shuttle Theory [J].
Brooks, George A. .
CELL METABOLISM, 2018, 27 (04) :757-785
[6]  
Chen YJ, 2016, NAT CHEM BIOL, V12, P937, DOI [10.1038/NCHEMBIO.2172, 10.1038/nchembio.2172]
[7]  
Ding L, 2018, CARCINOGENESIS
[8]   Lactate Metabolism in Human Lung Tumors [J].
Faubert, Brandon ;
Li, Kevin Y. ;
Cai, Ling ;
Hensley, Christopher T. ;
Kim, Jiyeon ;
Zacharias, Lauren G. ;
Yang, Chendong ;
Do, Quyen N. ;
Doucette, Sarah ;
Burguete, Daniel ;
Li, Hong ;
Huet, Giselle ;
Yuan, Qing ;
Wigal, Trevor ;
Butt, Yasmeen ;
Ni, Min ;
Torrealba, Jose ;
Oliver, Dwight ;
Lenkinski, Robert E. ;
Malloy, Craig R. ;
Wachsmann, Jason W. ;
Young, Jamey D. ;
Kernstine, Kemp ;
DeBerardinis, Ralph J. .
CELL, 2017, 171 (02) :358-+
[9]   Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay [J].
Fiaschi, Tania ;
Marini, Alberto ;
Giannoni, Elisa ;
Taddei, Maria Letizia ;
Gandellini, Paolo ;
De Donatis, Alina ;
Lanciotti, Michele ;
Serni, Sergio ;
Cirri, Paolo ;
Chiarugi, Paola .
CANCER RESEARCH, 2012, 72 (19) :5130-5140
[10]   Cancer-associated fibroblasts-heroes or villains? [J].
Gieniec, Krystyna A. ;
Butler, Lisa M. ;
Worthley, Daniel L. ;
Woods, Susan L. .
BRITISH JOURNAL OF CANCER, 2019, 121 (04) :293-302