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Single-cell imaging of the heat-shock response in colon cancer cells suggests that magnitude and length rather than time of onset determines resistance to apoptosis.

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posted on 22.11.2019 by Lavanya Ramapathiran, Tytus Bernas, Franziska Walter, Linda Williams, Heiko Düssmann, Caoimhín G. Concannon, Jochen HM Prehn

Targeting the proteasome is a valuable approach for cancer therapy, potentially limited by pro-survival pathways that are induced in parallel to cell death. Whether these pro-survival pathways are activated in all cells, show different activation kinetics in sensitive versus resistant cells or interact functionally with cell death pathways is unknown. We monitored activation of the heat-shock response (HSR), a key survival pathway induced by proteasome inhibition, relative to apoptosis activation in HCT116 colon cancer cells expressing enhanced green fluorescent protein (EGFP) under the control of the HSP70 promoter. Single-cell and high-content time-lapse imaging of epoxomicin treatment revealed that neither basal activity nor the time of onset of the HSR differed between resistant and sensitive populations. However, resistant cells had significantly higher and prolonged reporter activity than those that succumbed to cell death. p53 deficiency protected against cell death but failed to modulate the HSR. By contrast, inhibition of the HSR significantly increased the cytotoxicity of epoxomicin. Our data provide novel insights into the kinetics and heterogeneity of the HSR during proteasome inhibition, suggesting that the HSR modulates cell death signalling unidirectionally.

Funding

Science Foundation Ireland [grantnumber 08/IN1/1949]. Higher Education Authority [grant number RS/2006/183]. Health Research Board [grantnumber PHD/2007/1]. National Centre of Science, Poland[grant number NCN 2012/05/E/ST2/02180]

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The original article is available at http://jcs.biologists.org

Published Citation

Ramapathiran L, Bernas T, Walter F, Williams L, Düssmann H, Concannon CG, Prehn JH. Single-cell imaging of the heat-shock response in colon cancer cells suggests that magnitude and length rather than time of onset determines resistance to apoptosis. Journal of Cell Science. 2014;127(Pt 3):609-19.

Publication Date

01/02/2014

Publisher

Company of Biologists

PubMed ID

24284067

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