Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes

Xin Tong*, Kimberly A. Smith, Jill C. Pelling

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment. For the first time, we demonstrated that apigenin, a naturally occurring nonmutagenic flavonoid, induced AMPK activation in human keratinocytes (both cultured HaCaT cell line and primary normal human epidermal keratinocytes). Through experiments with over-expression of constitutively active Akt and knockdown of LKB1 expression by siRNAs, we further found that the activation of AMPK by apigenin was not dependent on its inhibition of Akt, and was independent of the activation of upstream kinase LKB1. Instead, another upstream kinase of AMPK, calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ), was required for apigenin-induced AMPK activation. We have demonstrated that knockdown of CaMKKβ expression by siRNA or inhibition of CaMKKβ activity by either CaMKK inhibitor STO-609 or BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester; a chelator of intracellular Ca 2+) prevented apigenin-induced AMPK activation. Apigenin-induced AMPK activation inhibited mTOR signaling and further induced autophagy in human keratinocytes. These results suggest that one of the mechanisms by which apigenin exerts its chemopreventive action may be through activation of AMPK and induction of autophagy in human keratinocytes.

Original languageEnglish (US)
Pages (from-to)268-279
Number of pages12
JournalMolecular Carcinogenesis
Issue number3
StatePublished - Mar 2012


  • AMPK
  • Apigenin
  • Autophagy
  • CaMKKβ
  • MTOR

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research


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