Open Access

TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation

  • Authors:
    • Giuseppina Bruno
    • Valeria Li Bergolis
    • Annamaria Piscazzi
    • Fabiana Crispo
    • Valentina Condelli
    • Pietro Zoppoli
    • Francesca Maddalena
    • Michele Pietrafesa
    • Guido Giordano
    • Danilo Swann Matassa
    • Franca Esposito
    • Matteo Landriscina
  • View Affiliations

  • Published online on: May 6, 2022     https://doi.org/10.3892/ijo.2022.5369
  • Article Number: 79
  • Copyright: © Bruno et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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)‑1α 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‑1α 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‑1α 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‑1α‑induced genetic/metabolic program under hypoxic conditions and may represent a promising target for novel metabolic therapies.
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June-2022
Volume 60 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Bruno G, Li Bergolis V, Piscazzi A, Crispo F, Condelli V, Zoppoli P, Maddalena F, Pietrafesa M, Giordano G, Matassa DS, Matassa DS, et al: TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation. Int J Oncol 60: 79, 2022
APA
Bruno, G., Li Bergolis, V., Piscazzi, A., Crispo, F., Condelli, V., Zoppoli, P. ... Landriscina, M. (2022). TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation. International Journal of Oncology, 60, 79. https://doi.org/10.3892/ijo.2022.5369
MLA
Bruno, G., Li Bergolis, V., Piscazzi, A., Crispo, F., Condelli, V., Zoppoli, P., Maddalena, F., Pietrafesa, M., Giordano, G., Matassa, D. S., Esposito, F., Landriscina, M."TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation". International Journal of Oncology 60.6 (2022): 79.
Chicago
Bruno, G., Li Bergolis, V., Piscazzi, A., Crispo, F., Condelli, V., Zoppoli, P., Maddalena, F., Pietrafesa, M., Giordano, G., Matassa, D. S., Esposito, F., Landriscina, M."TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation". International Journal of Oncology 60, no. 6 (2022): 79. https://doi.org/10.3892/ijo.2022.5369