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Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Oncogene volume 36, pages 3588–3598 (2017)Cite this article

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Abstract

Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

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Acknowledgements

The authors thank Mr Muhammad S Arif (Department of Public Health Sciences, University of California at Davis, Davis, CA, USA) for assistance with the experiments; Dr Yu-Ching Lin (UNIMED Healthcare Inc., Taiwan) and Ms Wen-Hsin Chang (Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan) for technological support in ForteBio system; Dr Guan-Chin Tseng (Department of Pathology, China Medical University Hospital, Taiwan) for useful advice; and the UC Davis Comprehensive Cancer Center Biorepository (University of California at Davis, Davis, CA, USA) for pathology support. This work was supported by NIH grants 1R01CA135401-01A1, 1R03CA181837-01 and 1R01DK082690-01A1, the Medical Service of the US Department of Veterans’ Affairs (all to RHW), and a research grant from Dialysis Clinic, Inc. (DCI# C-3917 to C-HC).

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA

    C-H Chen, E Yu, J F Trott & R H Weiss

  2. Comprehensive Cancer Center, University of California Davis, Davis, CA, USA

    C-H Chen & R H Weiss

  3. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L W R Fong

  4. Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, CA, USA

    E Yu & R Wu

  5. Department of Veterans’ Affairs Northern California Health Care System Center, Medical Service, Sacramento, CA, USA

    R H Weiss

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Correspondence to C-H Chen or R H Weiss.

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Chen, CH., Fong, L., Yu, E. et al. Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target. Oncogene 36, 3588–3598 (2017). https://doi.org/10.1038/onc.2016.510

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