Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK 4/6‐independent manner

Palbociclib, a CDK 4/6 inhibitor, has recently been approved for hormone receptor‐positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma ( HCC ), 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 . We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5′ AMP ‐activated protein kinase ( AMPK ) activation and protein phosphatase 5 ( PP 5) inhibition. Blockade of AMPK signals or ectopic expression of PP 5 counteracted the effect of palbociclib, confirming the involvement of the PP 5/ AMPK axis in palbociclib‐mediated HCC cell death. However, CDK 4/6 inhibition by lentivirus‐mediated sh RNA expression did not reproduce the effect of palbociclib‐treated cells, suggesting that the anti‐ HCC effect of palbociclib is independent of CDK 4/6. Moreover, two other CDK 4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP 5/ AMPK axis. Palbociclib also demonstrated significant tumor‐suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP 5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP 5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP 5/ AMPK axis independent of CDK 4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP 5/ AMPK signaling with a PP 5 inhibitor for the treatment of hepatocellular carcinoma.