Date of Award

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Robert E. Lewis

Abstract

Identification and characterization of pathways specific to tumor cell survival, but absent in normal tissues, provide opportunities to develop effective cancer therapies with reduced toxicity to the patient. Kinase suppressor of Ras 1 (KSR1) is required for the survival of colorectal cancer (CRC) cells, but dispensable in normal cells. Using KSR1 as a reference standard, we identified EPH (erythropoietin-producing hepatocellular carcinoma) receptor (EPHB4) as a KSR1 functional analog.

We show here that, like KSR1, EPHB4 is aberrantly overexpressed in human CRC cells and selectively required for their survival. Both 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 PGC1β protein via a post-transcriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression due to its ability to also elevate mRNA levels. Subsequent analysis of the post-transcriptional regulation demonstrates that KSR1 promotes the translation of Myc. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of CRC cells through regulation of Myc and PGC1β, suggesting that inhibition of these pathways should be selectively toxic to colorectal tumors.

We demonstrate that MEK inhibition reduced expression of Myc and PGC1β in CRC cells. To define the pathways that regulate expression of Myc and PGC1β, we examined the downstream effects of MEK1/2 substrates ERK1/2 and HSF1. Depletion of HSF1 increases Myc and PGC1β expression, while ERK1/2 inhibition decreases their expression.

The data presented here define multiple mechanisms regulating Myc and PGC1β expression, suggesting that tight regulation of this pathway is critical in normal cells. Aberrant expression of Myc and PGC1β contributes to the proliferation and survival of breast and renal cell carcinomas. We show that this pathway is also critical for CRC survival and is ERK-dependent. Together, these data reveal that tumor cells in various cancers require Myc-dependent expression of PGC1β to promote cell survival, which may be exploited in the development of new cancer therapeutics.

Available for download on Wednesday, April 25, 2018

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