{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T03:36:04Z","timestamp":1773113764133,"version":"3.50.1"},"reference-count":63,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2011,5,2]],"date-time":"2011-05-02T00:00:00Z","timestamp":1304294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>AMP\u2010activated 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\u2010expression 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\u2010dependent protein kinase kinase\u2010\u03b2 (CaMKK\u03b2), was required for apigenin\u2010induced AMPK activation. We have demonstrated that knockdown of CaMKK\u03b2 expression by siRNA or inhibition of CaMKK\u03b2 activity by either CaMKK inhibitor STO\u2010609 or BAPTA\u2010AM (1,2\u2010bis(2\u2010aminophenoxy)ethane\u2010<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032,<jats:italic>N<\/jats:italic>\u2032\u2010tetraacetic acid acetoxymethyl ester; a chelator of intracellular Ca<jats:sup>2+<\/jats:sup>) prevented apigenin\u2010induced AMPK activation. Apigenin\u2010induced 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. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/mc.20793","type":"journal-article","created":{"date-parts":[[2011,5,2]],"date-time":"2011-05-02T16:11:01Z","timestamp":1304352661000},"page":"268-279","source":"Crossref","is-referenced-by-count":51,"title":["Apigenin, a chemopreventive bioflavonoid, induces AMP\u2010activated protein kinase activation in human keratinocytes"],"prefix":"10.1002","volume":"51","author":[{"given":"Xin","family":"Tong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly A.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill 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