期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 60, 期 6, 页码 -出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2022.5369
关键词
TNF receptor-associated protein 1; hypoxia; hypoxia inducible factor 1 alpha; glycolysis; ribosome biosynthesis
类别
资金
- '5 per mille' 2018-2019 LILT Investigator
- PON AIM RI [2014-2020-1879351-2]
- Department of Medical and Surgical Sciences of the University of Foggia
- University of Foggia
The study reveals the role of the TRAP1 gene in the adaptive response of human colorectal cancer cells to hypoxia. TRAP1 is involved in regulating HIF-1α stabilization, glycolytic metabolism, and gene expression reprogramming. It also affects glucose uptake, lactate production, and ribosome biogenesis through the mTOR pathway.
Metabolic rewiring fuels rapid cancer cell proliferation by promoting adjustments in energetic resources, and increasing glucose uptake and its conversion into lactate, even in the presence of oxygen. Furthermore, solid tumors often contain hypoxic areas and can rapidly adapt to low oxygen conditions by activating hypoxia inducible factor (HIF)-1 alpha and several downstream pathways, thus sustaining cell survival and metabolic reprogramming. Since TNF receptor-associated protein 1 (TRAP1) is a HSP90 molecular chaperone upregulated in several human malignancies and is involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming, in the present study, its role was investigated in the adaptive response to hypoxia in human colorectal cancer (CRC) cells and organoids. In the present study, glucose uptake, lactate production and the expression of key metabolic genes were evaluated in TRAP1-silenced CRC cell models under conditions of hypoxia/normoxia. Whole genome gene expression profiling was performed in TRAP1-silenced HCT116 cells exposed to hypoxia to establish the role of TRAP1 in adaptive responses to oxygen deprivation. The results revealed that TRAP1 was involved in regulating hypoxia-induced HIF-1 alpha stabilization and glycolytic metabolism and that glucose transporter 1 expression, glucose uptake and lactate production were partially impaired in TRAP1-silenced CRC cells under hypoxic conditions. At the transcriptional level, the gene expression reprogramming of cancer cells driven by HIF-1 alpha was partially inhibited in TRAP1-silenced CRC cells and organoids exposed to hypoxia. Moreover, Gene Set Enrichment Analysis of TRAP1-silenced HCT116 cells exposed to hypoxia demonstrated that TRAP1 was involved in the regulation of ribosome biogenesis and this occurred with the inhibition of the mTOR pathway. Therefore, as demonstrated herein, TRAP1 is a key factor in maintaining HIF-1 alpha-induced genetic/metabolic program under hypoxic conditions and may represent a promising target for novel metabolic therapies.
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