FBP1 enhances the radiosensitivity by suppressing glycolysis via the FBXW7/mTOR axis in nasopharyngeal carcinoma cells

Life Sci. 2021 Oct 15;283:119840. doi: 10.1016/j.lfs.2021.119840. Epub 2021 Jul 20.

Abstract

Aims: The high glycolysis state of tumor cells is closely related to radioresistance. Fructose-1,6-bisphosphatase (FBP1) can regulate aerobic glycolysis and exerts tumor suppressor effects in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains to be investigated.

Materials and methods: RT-qPCR was used to measure FBP1 mRNA level. Glucose consumption, lactic acid production and ATP level was determined to evaluate glycolysis. The sensitivity of NPC cells to radiation was analyzed by MTT assay. Apoptosis was performed using flow cytometry. Gain- and loss-of function assays were carried out to explore the specific role of FBP1 and FBXW7 (F-box and WD repeat domain-containing 7) in NPC cell functions. The interactions between FBXW7 and FBP1 or mTOR were validated with co-immunoprecipitation assay. The in vivo experiments with xenografts were used to evaluate the role of FBP1 in tumor growth.

Key findings: FBP1 expression was lower in NPC tissues and cells than in normal controls and nasopharyngeal epithelial cells. Human recombinant FBP1 (rh-FBP1) treatment suppressed glycolysis in NPC cells. Besides, silencing FBP1 weakened the radiosensitivity and alleviated radiation-induced apoptosis and DNA damage by promoting glycolysis. Mechanism exploration found that FBP1 promoted FBXW7 protein level through suppressing the autoubiquitination of FBXW7. Then, FBXW7 restrained mTOR level by facilitating mTOR ubiquitination, thereby suppressing glycolysis and promoting radiation-induced apoptosis and DNA damage. Furthermore, overexpressing FBP1 in vivo hindered tumor growth and enhanced the antitumor activity of radiation.

Significance: FBP1 promoted the radiosensitivity in NPC cells by inhibiting glycolysis through the FBXW7/mTOR axis.

Keywords: FBP1; FBXW7/mTOR axis; Glycolysis; Nasopharyngeal carcinoma; Radiosensitivity.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Female
  • Fructose-Bisphosphatase / genetics
  • Fructose-Bisphosphatase / metabolism
  • Glycolysis*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Nasopharyngeal Carcinoma / genetics
  • Nasopharyngeal Carcinoma / metabolism*
  • Nasopharyngeal Carcinoma / pathology
  • Nasopharyngeal Carcinoma / radiotherapy
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / metabolism*
  • Nasopharyngeal Neoplasms / pathology
  • Nasopharyngeal Neoplasms / radiotherapy
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Radiation Tolerance*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Neoplasm Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • FBP1 protein, human
  • Fructose-Bisphosphatase