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

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 re...

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Veröffentlicht in:Molecular oncology 2017-08, Vol.11 (8), p.1035-1049
Hauptverfasser: Hsieh, Feng‐Shu, Chen, Yao‐Li, Hung, Man‐Hsin, Chu, Pei‐Yi, Tsai, Ming‐Hsien, Chen, Li‐Ju, Hsiao, Yung‐Jen, Shih, Chih‐Ting, Chang, Mao‐Ju, Chao, Tzu‐I, Shiau, Chung‐Wai, Chen, Kuen‐Feng
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container_end_page 1049
container_issue 8
container_start_page 1035
container_title Molecular oncology
container_volume 11
creator Hsieh, Feng‐Shu
Chen, Yao‐Li
Hung, Man‐Hsin
Chu, Pei‐Yi
Tsai, Ming‐Hsien
Chen, Li‐Ju
Hsiao, Yung‐Jen
Shih, Chih‐Ting
Chang, Mao‐Ju
Chao, Tzu‐I
Shiau, Chung‐Wai
Chen, Kuen‐Feng
description 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. Palbociclib is known as a CDK4/6 inhibitor and approved for the treatment of hormone receptor‐positive breast cancer. Here, we show that palbociclib exerts antitumor activity against hepatocellular carcinoma (HCC), but through a novel mechanism, inhibiting PP5 phosphatase and thus activating AMPK. PP5 expression in patients with HCC is associated with aggressive clinical features and thus might be a therapeutic target for HCC treatment.
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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. Palbociclib is known as a CDK4/6 inhibitor and approved for the treatment of hormone receptor‐positive breast cancer. Here, we show that palbociclib exerts antitumor activity against hepatocellular carcinoma (HCC), but through a novel mechanism, inhibiting PP5 phosphatase and thus activating AMPK. PP5 expression in patients with HCC is associated with aggressive clinical features and thus might be a therapeutic target for HCC treatment.</description><identifier>ISSN: 1574-7891</identifier><identifier>EISSN: 1878-0261</identifier><identifier>DOI: 10.1002/1878-0261.12072</identifier><identifier>PMID: 28453226</identifier><language>eng</language><publisher>United States: John Wiley &amp; Sons, Inc</publisher><subject>abemaciclib ; AMP-Activated Protein Kinases - metabolism ; AMPK ; Antimitotic agents ; Antineoplastic agents ; Apoptosis ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cyclin-Dependent Kinase 4 - metabolism ; Cyclin-Dependent Kinase 6 - metabolism ; Enzyme Activation - drug effects ; Ethylenediaminetetraacetic acid ; HCC ; Hepatoma ; Humans ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Medical equipment and supplies industry ; Medical test kit industry ; Neoplasm Proteins - metabolism ; palbociclib ; Phosphatases ; Piperazines - pharmacology ; PP5 ; Protein kinases ; Pyridines - pharmacology ; ribociclib ; Signal Transduction - drug effects</subject><ispartof>Molecular oncology, 2017-08, Vol.11 (8), p.1035-1049</ispartof><rights>2017 The Authors. 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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. Palbociclib is known as a CDK4/6 inhibitor and approved for the treatment of hormone receptor‐positive breast cancer. Here, we show that palbociclib exerts antitumor activity against hepatocellular carcinoma (HCC), but through a novel mechanism, inhibiting PP5 phosphatase and thus activating AMPK. 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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. Palbociclib is known as a CDK4/6 inhibitor and approved for the treatment of hormone receptor‐positive breast cancer. Here, we show that palbociclib exerts antitumor activity against hepatocellular carcinoma (HCC), but through a novel mechanism, inhibiting PP5 phosphatase and thus activating AMPK. PP5 expression in patients with HCC is associated with aggressive clinical features and thus might be a therapeutic target for HCC treatment.</abstract><cop>United States</cop><pub>John Wiley &amp; Sons, Inc</pub><pmid>28453226</pmid><doi>10.1002/1878-0261.12072</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4686-7019</orcidid><oa>free_for_read</oa></addata></record>
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subjects abemaciclib
AMP-Activated Protein Kinases - metabolism
AMPK
Antimitotic agents
Antineoplastic agents
Apoptosis
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Line, Tumor
Cyclin-Dependent Kinase 4 - metabolism
Cyclin-Dependent Kinase 6 - metabolism
Enzyme Activation - drug effects
Ethylenediaminetetraacetic acid
HCC
Hepatoma
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Medical equipment and supplies industry
Medical test kit industry
Neoplasm Proteins - metabolism
palbociclib
Phosphatases
Piperazines - pharmacology
PP5
Protein kinases
Pyridines - pharmacology
ribociclib
Signal Transduction - drug effects
title Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6‐independent manner
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