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Research ArticleArticle
Open Access

CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

Smit Kour, Sandeep Rana, Jacob I. Contreras, Hannah M. King, Caroline M. Robb, Yogesh A. Sonawane, Mourad Bendjennat, Ayrianne J. Crawford, Carter J. Barger, Smitha Kizhake, Xu Luo, Michael A. Hollingsworth and Amarnath Natarajan
Molecular Pharmacology October 2019, 96 (4) 419-429; DOI: https://doi.org/10.1124/mol.119.116855
Smit Kour
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Sandeep Rana
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Jacob I. Contreras
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Hannah M. King
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Caroline M. Robb
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Yogesh A. Sonawane
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Mourad Bendjennat
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Ayrianne J. Crawford
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Carter J. Barger
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Smitha Kizhake
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Xu Luo
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Michael A. Hollingsworth
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Amarnath Natarajan
Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Abstract

Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,1′-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 when combined with Bcl2 inhibitor results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 inhibitors.

SIGNIFICANCE STATEMENT Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.

Footnotes

    • Received April 5, 2019.
    • Accepted July 23, 2019.
  • ↵1 S.Ko., S.R., and J.I.C. contributed equally to this work.

  • This work was supported in part by the National Institutes of Health [Grants CA182820, CA197999, CA054807, CA009476, CA205496, CA036727, and GM118437] and fellowships from the University of Nebraska Medical Center (to J.I.C. and S.Ko.).

  • https://doi.org/10.1124/mol.119.116855.

  • Copyright © 2019 by The Author(s)

This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.

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Molecular Pharmacology: 96 (4)
Molecular Pharmacology
Vol. 96, Issue 4
1 Oct 2019
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Research ArticleArticle

CDK5 Inhibitor Sensitizes Cancer Cell Lines to Navitoclax

Smit Kour, Sandeep Rana, Jacob I. Contreras, Hannah M. King, Caroline M. Robb, Yogesh A. Sonawane, Mourad Bendjennat, Ayrianne J. Crawford, Carter J. Barger, Smitha Kizhake, Xu Luo, Michael A. Hollingsworth and Amarnath Natarajan
Molecular Pharmacology October 1, 2019, 96 (4) 419-429; DOI: https://doi.org/10.1124/mol.119.116855

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Research ArticleArticle

CDK5 Inhibitor Sensitizes Cancer Cell Lines to Navitoclax

Smit Kour, Sandeep Rana, Jacob I. Contreras, Hannah M. King, Caroline M. Robb, Yogesh A. Sonawane, Mourad Bendjennat, Ayrianne J. Crawford, Carter J. Barger, Smitha Kizhake, Xu Luo, Michael A. Hollingsworth and Amarnath Natarajan
Molecular Pharmacology October 1, 2019, 96 (4) 419-429; DOI: https://doi.org/10.1124/mol.119.116855
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