Abstract
Cancer cells up-regulate cell stress pathways, including the protein chaperone Hsp90. Increases in Hsp90 are believed "buffer" mutant protein activities necessary for cancer phenotypes. Activation of the cell stress pathway also alters the transcriptional landscape of cells in ways that are critical for cancer progression. However, it is unclear when and how the cell stress pathway is de-regulated during cancer progression. Here we report that mutations in adenomatous polyposis coli (APC) found in colorectal cancer activate cell stress pathways in mouse intestinal crypt cells, prior to loss of heterozygosity at APC or to the appearance of canonical intestinal cancer markers. Hsp90 levels are elevated in normal APC heterozygote crypt cells and further elevated in non-cancer cells adjacent to dysplasias, suggesting that the Hsp90 stress pathway marks the "cancer-field" effect. Expression of mutant APC in normal human epithelial cells is sufficient to activate a cell stress pathway via perturbations in microtubule dynamics. Inhibition of microtubule dynamics is sufficient to activate an Hsf1-dependent increase in gene transcription and protein levels. We suggest that the early activation of this Hsf1 dependent cell stress pathway by mono-allelic mutations in APC can affect cell programming in a way that contributes to cancer onset.
Highlights
The heat shock response is part of larger network of pathways that responds to cell stress and that plays an essential, conserved role in cellular adaptation following perturbations to cell homeostasis
To assess the temporal relationship between cell stress pathway activation and cancer onset, we analyzed the levels of Hsp90 in three regions in APCMin/+ mice that are representative of discreet disease states: (i) dysplastic regions are associated with early cancer and characterized by cell expansion, disorganized columnar epithelium, increases in β-catenin and loss of full length adenomatous polyposis coli (APC) (Figure 1A–1B, arrow); (ii) regions adjacent to dysplasias, usually within 1–20 cell equivalents that appear otherwise normal; (iii) normal intestinal crypts found approximately 10 crypt distances away from any dysplasia
We have identified a novel link between a cancer driver mutation in the tumor suppressor gene, adenomatous polyposis coli, and the activation of a cell stress pathway, a state that precedes cancer in the intestine and anticipates the mature cancer phenotype found in carcinomas
Summary
The heat shock response is part of larger network of pathways that responds to cell stress and that plays an essential, conserved role in cellular adaptation following perturbations to cell homeostasis. Cells lacking HSF1, the master transcriptional regulator of the heat shock pathway, are refractory to transformation by variety of oncogenes [1, 3]. These findings suggest a role for the heat shock pathway in cancer initiation or progression. Hsp has been proposed to act as a “buffer” to maintain the activity of mutated oncogenes Support for this idea comes from the ability of Hps to interact with and stabilize a wide-range of oncogenic proteins (e.g., v-Src and Raf) [2, 4,5,6,7,8]. Cancer cells may have a large number of Hsp targets, an idea supported by the complexity of the Hsp90-interactome [13,14,15,16], and by the finding that a larger percentage of Hsp is in an active conformation in cancer cells [17,18,19]
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