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Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis

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Abstract

Despite the current progress in cancer research and therapy, breast cancer remains the leading cause of mortality among half a million women worldwide. Migration and invasion of cancer cells are associated with prevalent tumor metastasis as well as high mortality. Extensive studies have powerfully established the role of prototypic second messenger cAMP and its two ubiquitously expressed intracellular cAMP receptors namely the classic protein kinaseA/cAMP-dependent protein kinase (PKA) and the more recently discovered exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (EPAC/cAMP-GEF) in cell migration, cell cycle regulation, and cell death. Herein, we performed the analysis of the Cancer Genome Atlas (TCGA) dataset to evaluate the essential role of cAMP molecular network in breast cancer. We report that EPAC1, PKA, and AKAP9 along with other molecular partners are amplified in breast cancer patients, indicating the importance of this signaling network. To evaluate the functional role of few of these proteins, we used pharmacological modulators and analyzed their effect on cell migration and cell death in breast cancer cells. Hence, we report that inhibition of EPAC1 activity using pharmacological modulators leads to inhibition of cell migration and induces cell death. Additionally, we also observed that the inhibition of EPAC1 resulted in disruption of its association with the microtubule cytoskeleton and delocalization of AKAP9 from the centrosome as analyzed by in vitro imaging. Finally, this study suggests for the first time the mechanistic insights of mode of action of a primary cAMP-dependent sensor, Exchange protein activated by cAMP 1 (EPAC1), via its interaction with A-kinase anchoring protein 9 (AKAP9). This study provides a new cell signaling cAMP–EPAC1–AKAP9 direction to the development of additional biotherapeutics for breast cancer.

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Abbreviations

AKAP:

A-kinase anchoring protein

PKA:

Protein kinase A

EPAC:

Exchange protein activated by cAMP

TCGA:

The Cancer Genome Atlas

ESI:

EPAC-specific inhibitor

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Acknowledgements

Seema Sehrawat is the recipient of BioCARe Award from Department of Biotechnology, Govt. of India and acknowledges the funding support. Shailja Singh acknowledges DBT PILOT project grant on cancer. Shiv Nadar Foundation is acknowledged for providing the Ph.D. fellowship to Mr. Naveen Kumar. Dr. Sonal Gupta is the recipient of University Grant Commission Postdoctoral fellowship For Women. We would like to thank Dr. Sunita Setlur, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and Dr. Chandan Kumar-Sinha, Michigan Center for Translational Pathology, University of Michigan, and Ann Arbor, MI, USA for their advice on TCGA analysis. The TCGA analysis was performed using the breast cancer data available for the cbioportal. The results presented in this study are partly based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. We also sincerely thank the financial support received from LRE JNU and ICMR CAR 2016 -17.

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Authors and Affiliations

  1. Brain Metastasis and NeuroVascular Disease Modeling Lab, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NCR, India

    Naveen Kumar & Seema Sehrawat

  2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Seema Sehrawat

  3. Host Pathogen Interactions and Disease Modeling Group, Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, NCR, India

    Sonal Gupta & Shailja Singh

  4. Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India

    Sonal Gupta & Shailja Singh

  5. International Center for Genetic Engineering and Biotechnology, New Delhi, 110067, India

    Surbhi Dabral

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  1. Naveen Kumar
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  2. Sonal Gupta
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  3. Surbhi Dabral
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Correspondence to Shailja Singh or Seema Sehrawat.

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Naveen Kumar and Sonal Gupta—equal first author.

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Kumar, N., Gupta, S., Dabral, S. et al. Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis. Mol Cell Biochem 430, 115–125 (2017). https://doi.org/10.1007/s11010-017-2959-3

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  • DOI: https://doi.org/10.1007/s11010-017-2959-3

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