Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance
Qingzhu Shi 1, Qicong Shen 2, Yanfang Liu
3, Yang Shi 1, Wenwen Huang 4, Xi Wang 4, Zhiqing Li 2, Yangyang Chai 5, Hao
Wang 6, Xiangjia Hu 2, Nan Li 2, Qian Zhang 7, Xuetao Cao 8
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Cancer Cell.2022 Aug
30;S1535-6108(22)00376-2. doi: 10.1016/j.ccell.2022.08.012.
PMID: 36084651
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Abstract
How
glucose metabolism remodels pro-tumor functions of tumor-associated macrophages
(TAMs) needs further investigation. Here we show that M2-like TAMs bear the
highest individual capacity to take up intratumoral glucose. Their increased
glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation
to promote cancer metastasis and chemoresistance. Glucose metabolism promotes
O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine
210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating
mature Cathepsin B in macrophages and its secretion in the tumor
microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and
mature Cathepsin B in the TME and disrupts cancer metastasis and
chemoresistance. Human TAMs with high OGT are positively correlated with
Cathepsin B expression, and both levels predict chemotherapy response and
prognosis of individuals with cancer. Our study reports the biological and
potential clinical significance of glucose metabolism in tumor-promoting TAMs
and reveals insights into the underlying mechanisms.
