Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer
Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell...
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| Published in | Molecular cancer therapeutics Vol. 14; no. 3; pp. 642 - 648 |
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| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
01.03.2015
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| Abstract | Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy. |
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| AbstractList | Heat shock protein 70 (Hsp70) is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a non-canonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has anti-proliferative activity (EC
50
values between 0.3 and 4 μM) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. Based on these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anti-cancer therapy. Abstract Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70–Bag3 protein–protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70–Bag3 interaction may be a promising, new target for anticancer therapy. Mol Cancer Ther; 14(3); 642–8. ©2015 AACR. Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven relatively challenging, driving interest in alternative approaches. Hsp70 collaborates with the Bcl2-associated athanogene 3 (Bag3) to promote cell survival through multiple pathways, including FoxM1. Therefore, inhibitors of the Hsp70-Bag3 protein-protein interaction (PPI) may provide a noncanonical way to target this chaperone. We report that JG-98, an allosteric inhibitor of this PPI, indeed has antiproliferative activity (EC50 values between 0.3 and 4 μmol/L) across cancer cell lines from multiple origins. JG-98 destabilized FoxM1 and relieved suppression of downstream effectors, including p21 and p27. On the basis of these findings, JG-98 was evaluated in mice for pharmacokinetics, tolerability, and activity in two xenograft models. The results suggested that the Hsp70-Bag3 interaction may be a promising, new target for anticancer therapy. |
| Author | Aftab, Blake T Acosta-Alvear, Diego Rauch, Jennifer N Cho, Min Li, Xiaokai Gestwicki, Jason E Murnane, Megan Kampmann, Martin Colvin, Teresa Dunyak, Bryan Hann, Byron Walter, Peter Sherman, Michael Y Weissman, Jonathan S |
| AuthorAffiliation | 3 Howard Hughes Medical Institute, University of California at San Francisco, Department of Biochemistry and Biophysics, San Francisco, CA 94158 1 University of California at San Francisco, Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, San Francisco, CA 94158 5 University of California at San Francisco, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158 4 Howard Hughes Medical Institute, University of California at San Francisco, Department of Molecular and Cellular Pharmacology, San Francisco, CA 94158 2 Boston University School of Medicine, Department of Biochemistry, Boston, MA 02118 |
| AuthorAffiliation_xml | – name: 4 Howard Hughes Medical Institute, University of California at San Francisco, Department of Molecular and Cellular Pharmacology, San Francisco, CA 94158 – name: 3 Howard Hughes Medical Institute, University of California at San Francisco, Department of Biochemistry and Biophysics, San Francisco, CA 94158 – name: 1 University of California at San Francisco, Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, San Francisco, CA 94158 – name: 2 Boston University School of Medicine, Department of Biochemistry, Boston, MA 02118 – name: 5 University of California at San Francisco, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158 |
| Author_xml | – sequence: 1 givenname: Xiaokai surname: Li fullname: Li, Xiaokai organization: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California – sequence: 2 givenname: Teresa surname: Colvin fullname: Colvin, Teresa organization: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts – sequence: 3 givenname: Jennifer N surname: Rauch fullname: Rauch, Jennifer N organization: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California – sequence: 4 givenname: Diego surname: Acosta-Alvear fullname: Acosta-Alvear, Diego organization: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California – sequence: 5 givenname: Martin surname: Kampmann fullname: Kampmann, Martin organization: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California – sequence: 6 givenname: Bryan surname: Dunyak fullname: Dunyak, Bryan organization: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California – sequence: 7 givenname: Byron surname: Hann fullname: Hann, Byron organization: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California – sequence: 8 givenname: Blake T surname: Aftab fullname: Aftab, Blake T organization: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California – sequence: 9 givenname: Megan surname: Murnane fullname: Murnane, Megan organization: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California – sequence: 10 givenname: Min surname: Cho fullname: Cho, Min organization: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California – sequence: 11 givenname: Peter surname: Walter fullname: Walter, Peter organization: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California – sequence: 12 givenname: Jonathan S surname: Weissman fullname: Weissman, Jonathan S organization: Department of Molecular and Cellular Pharmacology, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California – sequence: 13 givenname: Michael Y surname: Sherman fullname: Sherman, Michael Y organization: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts – sequence: 14 givenname: Jason E surname: Gestwicki fullname: Gestwicki, Jason E email: Jason.Gestwicki@ucsf.edu organization: Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California. Jason.Gestwicki@ucsf.edu |
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| Snippet | Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has proven... Abstract Hsp70 is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of Hsp70 has... Heat shock protein 70 (Hsp70) is a stress-inducible molecular chaperone that is required for cancer development at several steps. Targeting the active site of... |
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| SubjectTerms | Adaptor Proteins, Signal Transducing - metabolism Animals Antineoplastic Agents - pharmacology Apoptosis Regulatory Proteins - metabolism Cell Line, Tumor Cell Proliferation - drug effects Cyclin-Dependent Kinase Inhibitor p21 - metabolism Forkhead Box Protein M1 Forkhead Transcription Factors - metabolism Gene Expression Regulation, Neoplastic - drug effects HeLa Cells HSP70 Heat-Shock Proteins - metabolism HT29 Cells Humans MCF-7 Cells Mice Proliferating Cell Nuclear Antigen - metabolism Protein Interaction Domains and Motifs - physiology |
| Title | Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer |
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