Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes
In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a...
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| Published in | Cancer science Vol. 111; no. 6; pp. 2132 - 2145 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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England
John Wiley & Sons, Inc
01.06.2020
John Wiley and Sons Inc |
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| Abstract | In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes.
We found that abemaciclib, a CDK4/6 inhibitor, exerted a potent cytocidal effect in cancer cell lines with an atypical cell death phenotype, which entailed formation of multiple cytoplasmic vacuoles, and both the formation of vacuoles and the induction of cell death were inhibited by V‐ATPase inhibitors. Precise live‐cell imaging and transmission electron microscopy revealed that these vacuoles were derived from lysosomes that expanded following acidification and contained undigested debris and remnants of organelles. Thus we here propose a unique form of cell death accompanied by swollen and dysfunctional lysosomes by abemaciclib treatment. |
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| AbstractList | In the cell cycle, the G1 /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1 /S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non-small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell-death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell-death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar-type ATPase (V-ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live-cell imaging revealed that the abemaciclib-induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes.In the cell cycle, the G1 /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1 /S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non-small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell-death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell-death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar-type ATPase (V-ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live-cell imaging revealed that the abemaciclib-induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. In the cell cycle, the G /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates the G /S transition, leading to oncogenic transformation. We found that three CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G phase in cancer cell lines, including A549 human non-small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however, vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar-type ATPase (V-ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live-cell imaging revealed that the abemaciclib-induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization was occurred after abemaciclib treatment. Together, these results indicate that in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. In the cell cycle, the G 1 /S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G 1 /S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G 1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. In the cell cycle, the G 1 /S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G 1 /S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G 1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. We found that abemaciclib, a CDK4/6 inhibitor, exerted a potent cytocidal effect in cancer cell lines with an atypical cell death phenotype, which entailed formation of multiple cytoplasmic vacuoles, and both the formation of vacuoles and the induction of cell death were inhibited by V‐ATPase inhibitors. Precise live‐cell imaging and transmission electron microscopy revealed that these vacuoles were derived from lysosomes that expanded following acidification and contained undigested debris and remnants of organelles. Thus we here propose a unique form of cell death accompanied by swollen and dysfunctional lysosomes by abemaciclib treatment. In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes. We found that abemaciclib, a CDK4/6 inhibitor, exerted a potent cytocidal effect in cancer cell lines with an atypical cell death phenotype, which entailed formation of multiple cytoplasmic vacuoles, and both the formation of vacuoles and the induction of cell death were inhibited by V‐ATPase inhibitors. Precise live‐cell imaging and transmission electron microscopy revealed that these vacuoles were derived from lysosomes that expanded following acidification and contained undigested debris and remnants of organelles. Thus we here propose a unique form of cell death accompanied by swollen and dysfunctional lysosomes by abemaciclib treatment. |
| Author | Hino, Hirotsugu Iriyama, Noriyoshi Moriya, Shota Kokuba, Hiroko Miyazawa, Keisuke Kazama, Hiromi Aizawa, Shin Takano, Naoharu Hiramoto, Masaki |
| AuthorAffiliation | 3 Division of Hematology and Rheumatology Department of Medicine Nihon University School of Medicine Tokyo Japan 2 Division of Anatomical Science Department of Functional Morphology Nihon University School of Medicine Tokyo Japan 1 Department of Biochemistry Tokyo Medical University Tokyo Japan 4 Joint Research Center for Basic Medical Science Tokyo Medical University Tokyo Japan |
| AuthorAffiliation_xml | – name: 4 Joint Research Center for Basic Medical Science Tokyo Medical University Tokyo Japan – name: 3 Division of Hematology and Rheumatology Department of Medicine Nihon University School of Medicine Tokyo Japan – name: 2 Division of Anatomical Science Department of Functional Morphology Nihon University School of Medicine Tokyo Japan – name: 1 Department of Biochemistry Tokyo Medical University Tokyo Japan |
| Author_xml | – sequence: 1 givenname: Hirotsugu orcidid: 0000-0001-7560-2442 surname: Hino fullname: Hino, Hirotsugu organization: Nihon University School of Medicine – sequence: 2 givenname: Noriyoshi surname: Iriyama fullname: Iriyama, Noriyoshi organization: Nihon University School of Medicine – sequence: 3 givenname: Hiroko surname: Kokuba fullname: Kokuba, Hiroko organization: Tokyo Medical University – sequence: 4 givenname: Hiromi surname: Kazama fullname: Kazama, Hiromi organization: Tokyo Medical University – sequence: 5 givenname: Shota surname: Moriya fullname: Moriya, Shota organization: Tokyo Medical University – sequence: 6 givenname: Naoharu surname: Takano fullname: Takano, Naoharu organization: Tokyo Medical University – sequence: 7 givenname: Masaki surname: Hiramoto fullname: Hiramoto, Masaki organization: Tokyo Medical University – sequence: 8 givenname: Shin surname: Aizawa fullname: Aizawa, Shin organization: Nihon University School of Medicine – sequence: 9 givenname: Keisuke orcidid: 0000-0002-8435-1304 surname: Miyazawa fullname: Miyazawa, Keisuke email: miyazawa@tokyo-med.ac.jp organization: Tokyo Medical University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32304130$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This article is protected by copyright. All rights reserved. 2020. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. |
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| Keywords | vacuole formation V-ATPase lysosome abemaciclib CDK4/6 inhibitor |
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| Snippet | In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates... In the cell cycle, the G 1 /S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6... In the cell cycle, the G /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates... In the cell cycle, the G1 /S transition is controlled by the cyclin-dependent kinase (CDK) 4/6-cyclin D complex. Constitutive activation of CDK4/6 dysregulates... |
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| SubjectTerms | abemaciclib Acidification Adenosine triphosphatase Alzheimer's disease Apoptosis Autophagy Breast cancer Cancer therapies CDK4/6 inhibitor Cell cycle Cell death Cell growth Concanamycin A Cyclin D Cyclin-dependent kinase 4 Cycloheximide Cytotoxicity Dextran G1 phase Genotype & phenotype Kinases Lung cancer lysosome Lysosomes Morphology Necroptosis Non-small cell lung carcinoma Organelles Original Phagocytosis Phagosomes Phenotypes Phosphorylation Proteins Transcription factors Transmission electron microscopy Tumor cell lines vacuole formation Vacuoles V‐ATPase |
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| Title | Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes |
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