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G protein-coupled receptor kinase 2 modifies the cellular reaction to cisplatin through interactions with NADPH oxidase 4

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Abstract

G protein-coupled receptor kinases (GRKs), in addition to their role in modulating signal transduction mechanisms associated with activated G protein-coupled receptors (GPCRs), can also interact with many non-GPCR proteins to mediate cellular responses to chemotherapeutics. The rationale for this study is based on the presumption that GRK2 modulates the responses of cancer cells to the chemotherapeutic cisplatin. In this report, we show that GRK2 modulates the responses of cancer cells to cisplatin. Cervical cancer HeLa cells stably transfected with GRK2 shRNA, to decrease GRK2 protein expression, show increased sensitivity to cisplatin. Of interest, these cells also show increased accumulation of NADPH, associating with decreased NADP buildup, at low concentrations of cisplatin tested. These changes in NADPH and NADP levels are also observed in the breast cancer MDA MB 231 cells, which has lower endogenous GRK2 protein expression levels, but not BT549, a breast cancer cell line with higher GRK2 protein expression. This effect of NADPH accumulation may be associated with a decrease in NADPH oxidase 4 (NOX4) protein expression, which is found to correlate with GRK2 protein expression in cancer cells—a relationship which mimics that observed in cardiomyocytes. Furthermore, like in cardiomyocytes, GRK2 and NOX4 interact to form complexes in cancer cells. Collectively, these results suggest that GRK2 interacts with NOX4 to modify cisplatin sensitivity in cancer cells and may also factor into the success of cisplatin-based regimens.

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Data Availability

The data that support the findings of this study are available from the corresponding author [CS] upon reasonable request.

Abbreviations

GRK:

G protein-coupled receptor kinase

GPCRs:

G protein-coupled receptors

HDAC:

Histone deacetylase

NOX4:

NADPH oxidase 4

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Acknowledgements

We like to thank Dr. Murat Alp and Deniz Alp for critical review of the manuscript. This work was partly funded by the Roseman University of Health Sciences College of Pharmacy Intramural Grant.

Funding

The funding of this work was provided by Roseman University of Health Sciences College of Pharmacy and the Roseman University of Health Sciences College of Pharmacy Intramural Grant Award.

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  1. Roseman University of Health Sciences School of Pharmacy, Henderson, NV, 89014, USA

    Jane C. Ammon, Danielle Valls, Mohamed Eldemerdash, Jigisha R. Patel, Philip D. Tran, Lifeng Feng, Michael Gi, Trang T. Gonzalez, Chuc Phan, Ashley E. Zendejas & Christopher H. So

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  1. Jane C. Ammon
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Ammon, J.C., Valls, D., Eldemerdash, M. et al. G protein-coupled receptor kinase 2 modifies the cellular reaction to cisplatin through interactions with NADPH oxidase 4. Mol Cell Biochem 476, 1505–1516 (2021). https://doi.org/10.1007/s11010-020-03969-3

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