Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo

Cancer Lett. 2019 Feb 1:442:126-136. doi: 10.1016/j.canlet.2018.10.016. Epub 2018 Nov 2.

Abstract

Gossypetin as a hexahydroxylated flavonoid found in many flowers and Hibiscus. It exerts various pharmacological activities, including antioxidant, antibacterial and anticancer activities. However, the anticancer capacity of gossypetin has not been fully elucidated. In this study, gossypetin was found to inhibit anchorage-dependent and -independent growth of esophageal cancer cells. To identify the molecular target(s) of gossypetin, various signaling protein kinases were screened and results indicate that gossypetin strongly attenuates the MKK3/6-p38 signaling pathway by directly inhibiting MKK3 and MKK6 protein kinase activity in vitro. Mechanistic investigations showed that arginine-61 in MKK6 is critical for binding with gossypetin. Additionally, the inhibition of cell growth by gossypetin is dependent on the expression of MKK3 and MKK6. Gossypetin caused G2 phase cell cycle arrest and induced intrinsic apoptosis by activating caspases 3 and 7 and increasing the expression of BAX and cytochrome c. Notably, gossypetin suppressed patient-derived esophageal xenograft tumor growth in an in vivo mouse model. Our findings suggest that gossypetin is an MKK3 and MKK6 inhibitor that could be useful for preventing or treating esophageal cancer.

Keywords: Esophageal cancer; Gossypetin; MKK3/6; Patient-derived xenograft; p38.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / enzymology
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma / drug therapy*
  • Esophageal Squamous Cell Carcinoma / enzymology
  • Esophageal Squamous Cell Carcinoma / pathology
  • Female
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • MAP Kinase Kinase 3 / antagonists & inhibitors*
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase 6 / antagonists & inhibitors*
  • MAP Kinase Kinase 6 / chemistry
  • MAP Kinase Kinase 6 / metabolism
  • Mice, SCID
  • Molecular Docking Simulation
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Flavonoids
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • MAP2K3 protein, human
  • MAP2K6 protein, human
  • gossypetin