Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target.
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.
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA.|Comprehensive Cancer Center, University of California Davis, Davis, CA, USA.
C-H
CH
Chen
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
L W R
LWR
Fong
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA.|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
E
Yu
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.
R
R
Wu
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA.
J F
JF
Trott
Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA, USA.|Comprehensive Cancer Center, University of California Davis, Davis, CA, USA.|Medical Service, Department of Veterans' Affairs Northern California Health Care System Center, Sacramento, CA, USA.
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RH
Weiss
D000328:Adult; D000368:Aged; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010671:Phenylurea Compounds / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C559147:regorafenib; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases