Sulforaphane Inhibits Nonmuscle Invasive Bladder Cancer Cells Proliferation through Suppression of HIF-1α-Mediated Glycolysis in Hypoxia

J Agric Food Chem. 2019 Jul 17;67(28):7844-7854. doi: 10.1021/acs.jafc.9b03027. Epub 2019 Jul 9.

Abstract

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 μM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.

Keywords: HIF-1α; bladder cancer; glycolysis; hypoxia; sulforaphane.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Glycolysis / drug effects
  • Humans
  • Hypoxia / drug therapy
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia / physiopathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Isothiocyanates / administration & dosage*
  • Oxygen / metabolism
  • Signal Transduction / drug effects
  • Sulfoxides
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / physiopathology*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isothiocyanates
  • Sulfoxides
  • sulforaphane
  • Oxygen