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

Xiaomeng Xie, Kangdong Liu, Feifei Liu, Hanyong Chen, Xiangyu Wang, Xueyin Zu, Xiaoli Ma, Ting Wang, Qiong Wu, Yan Zheng, Ann M. Bode, Zigang Dong, Dong Joon Kim

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)126-136
Number of pages11
JournalCancer Letters
StatePublished - Feb 1 2019

Bibliographical note

Funding Information:
This work was supported by Key program of Henan Province, China [grant number 161100510300 ] and National Natural Science Foundation of China [grant number 81572812 ].

Publisher Copyright:
© 2018 Elsevier B.V.


  • Esophageal cancer
  • Gossypetin
  • MKK3/6
  • p38
  • Patient-derived xenograft

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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