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The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC<\/jats:styled-content>), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC<\/jats:styled-content>. We found that palbociclib induced both autophagy and apoptosis in HCC<\/jats:styled-content> cells through a mechanism involving 5\u2032 AMP<\/jats:styled-content>\u2010activated protein kinase (AMPK<\/jats:styled-content>) activation and protein phosphatase 5 (PP<\/jats:styled-content>5) inhibition. Blockade of AMPK<\/jats:styled-content> signals or ectopic expression of PP<\/jats:styled-content>5 counteracted the effect of palbociclib, confirming the involvement of the PP<\/jats:styled-content>5\/AMPK<\/jats:styled-content> axis in palbociclib\u2010mediated HCC<\/jats:styled-content> cell death. However, CDK<\/jats:styled-content>4\/6 inhibition by lentivirus\u2010mediated shRNA<\/jats:styled-content> expression did not reproduce the effect of palbociclib\u2010treated cells, suggesting that the anti\u2010HCC<\/jats:styled-content> effect of palbociclib is independent of CDK<\/jats:styled-content>4\/6. Moreover, two other CDK<\/jats:styled-content>4\/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC<\/jats:styled-content> cell viability and the PP<\/jats:styled-content>5\/AMPK<\/jats:styled-content> axis. Palbociclib also demonstrated significant tumor\u2010suppressive activity in a HCC<\/jats:styled-content> xenograft model, which was associated with upregulation of pAMPK<\/jats:styled-content> and PP<\/jats:styled-content>5 inhibition. Finally, we analyzed 153 HCC<\/jats:styled-content> clinical samples and found that PP<\/jats:styled-content>5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC<\/jats:styled-content> through the PP<\/jats:styled-content>5\/AMPK<\/jats:styled-content> axis independent of CDK<\/jats:styled-content>4\/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP<\/jats:styled-content>5\/AMPK<\/jats:styled-content> signaling with a PP<\/jats:styled-content>5 inhibitor for the treatment of hepatocellular carcinoma.<\/jats:p>","DOI":"10.1002\/1878-0261.12072","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T14:05:10Z","timestamp":1493388310000},"page":"1035-1049","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Palbociclib induces activation of AMPK<\/scp> and inhibits hepatocellular carcinoma in a CDK<\/scp>4\/6\u2010independent manner"],"prefix":"10.1002","volume":"11","author":[{"given":"Feng\u2010Shu","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital Taipei Taiwan"},{"name":"National Center of Excellence for Clinical Trial and Research National 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