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Protein kinase CK2 impact on intracellular calcium homeostasis in prostate cancer

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Abstract

Protein kinase CK2 plays multiple roles in cell function in normal and disease states. CK2 is elevated in numerous types of cancer cells, and CK2 suppression of apoptosis represents a key link to the cancer cell phenotype. CK2 regulation of cell survival and death involves diverse processes, and our previous work suggested that mitochondrial machinery is a key locus of this function. One of the earliest responses of prostate cells to inhibition of CK2 is a change in mitochondrial membrane potential, possibly associated with Ca2+ signaling. Thus, in the present work, we investigated early impact of CK2 on intracellular Ca2+ dynamics. Three prostate cancer (PCa) cell lines, PC3-LN4, C4-2B, and 22Rv1, were studied. PCa cells were treated with the CK2 small molecule inhibitors 4,5,6,7-tetrabrombenzotriazole and CX-4945 followed by analysis of Ca2+ levels in various cellular compartments over time. The results showed dose-dependent loss in cytosolic Ca2+ levels starting within 2 min and reaching maximal loss within 5–10 min. There was a concomitant increase in Ca2+ in the endoplasmic reticulum (ER) and mitochondrial compartments. The results suggest that inhibition of CK2 activity results in a rapid movement of Ca2+ out of the cytosol and into the ER and mitochondria, which may be among the earliest contributory factors for induction of apoptosis in cells subjected to inhibition of CK2. In cells with death-inducing levels of CK2 inhibition, total cellular Ca2+ levels dropped at 2 h post-treatment. These novel observations represent a potential mechanism underlying regulation of cell survival and death by CK2 activity.

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Acknowledgements

KA holds the title of Senior Research Career Scientist awarded by the U.S. Department of Veterans Affairs. M.A. was recipient of a scholarship awarded by the Higher Education Commission of Pakistan.

Disclaimer

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs or the U.S. government.

Funding

This work was supported by Merit Review research funds BX003282 awarded by the Department of Veterans Affairs (K.A.), and research grant R01CA150182 awarded by the National Cancer Institute, NIH, Department of Health and Human Services (K.A.).

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Author notes

  1. Janeen H. Trembley and Khalil Ahmed are Co-senior authors.

Authors and Affiliations

  1. Research Service, Minneapolis VA Health Care System, Minneapolis, MN, 55417, USA

    Muhammad Afzal, Betsy T. Kren, Janeen H. Trembley & Khalil Ahmed

  2. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

    Muhammad Afzal, Janeen H. Trembley & Khalil Ahmed

  3. Department of Biochemistry, Riphah International University, Islamabad, Pakistan

    Muhammad Afzal & A. Khaliq Naveed

  4. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA

    Betsy T. Kren, Janeen H. Trembley & Khalil Ahmed

  5. Department of Urology, University of Minnesota, Minneapolis, MN, 55455, USA

    Khalil Ahmed

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  1. Muhammad Afzal
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  3. A. Khaliq Naveed
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Contributions

Conceptualization, MA, JHT, KA; methodology, MA, JHT, BTK, KA; experimental work, MA, JHT; statistical analysis, MA, JHT; discussion of results and data, MA, JHT, BTK, AKN, KA; manuscript preparation, MA, JHT, KA; final review and editing, MA, JHT, BTK, AKN, KA; funding acquisition, KA.

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Correspondence to Khalil Ahmed.

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Afzal, M., Kren, B.T., Naveed, A.K. et al. Protein kinase CK2 impact on intracellular calcium homeostasis in prostate cancer. Mol Cell Biochem 470, 131–143 (2020). https://doi.org/10.1007/s11010-020-03752-4

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