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Mol Oncol. 2017 Aug;11(8):1035-1049. doi: 10.1002/1878-0261.12072. Epub 2017 May 15.

Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6-independent manner.

Author information

1
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
2
National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
3
Department of Surgery, Changhua Christian Hospital, Taiwan.
4
School of Medicine, Kaohsiung Medical University, Taiwan.
5
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.
6
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
7
Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.
8
School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.
9
Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Taiwan.
10
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.

Abstract

Palbociclib, a CDK4/6 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 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib-mediated HCC cell death. However, CDK4/6 inhibition by lentivirus-mediated shRNA expression did not reproduce the effect of palbociclib-treated cells, suggesting that the anti-HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor-suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 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 PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.

KEYWORDS:

AMPK ; HCC ; PP5; abemaciclib; palbociclib; ribociclib

PMID:
28453226
PMCID:
PMC5537702
DOI:
10.1002/1878-0261.12072
[Indexed for MEDLINE]
Free PMC Article

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