KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors.
Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Jamie L
JL
McCall
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Drew
D
Gehring
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Beth K
BK
Clymer
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Kurt W
KW
Fisher
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Binita
B
Das
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
David L
DL
Kelly
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Hyunseok
H
Kim
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Michael A
MA
White
Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA rlewis@unmc.edu.
Robert E
RE
Lewis
D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins; D036224:Receptor, EphB4 / Q000378:metabolism*; D015854:Up-Regulation
D002352:Carrier Proteins; C489427:MYC protein, human; C455622:PPARGC1B protein, human; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D036224:Receptor, EphB4