The proteasome is a multisubunit enzyme complex responsible for degrading proteins, and has become an important therapeutic target for cancer treatment. One of the limitations to this approach, however, is that proteasome inhibitors induce pro-survival pathways, such as the heat-shock response (HSR), in parallel to cell death; indeed, the expression of heat-shock proteins (HSPs) has been shown to enhance the growth and survival of tumours. Here (p. 609), Jochen Prehn and colleagues monitored activation of the HSR in real time relative to activation of apoptosis. They created a colon cancer cell line that expresses enhanced green fluorescent protein (EGFP) under the control of the HSP70 (HSPA1A) promoter. Using a combination of single-cell and high-content time-lapse imaging, the authors investigate, in real time, the activation of the HSP70 promoter following proteasome inhibition with epoxomicin relative to whether the cells survive treatment. Resistant and sensitive cell populations did not differ in basal activity or the time of onset of the HSR, but resistant cells did show higher levels of HSP70 induction for more prolonged periods of time compared with sensitive cells. p53-deficient cells were protected against cell death, but did not show any change in HSP70 levels compared with wild-type cells; inhibiting the HSR in the presence of the proteasome inhibitor, however, increased the cytotoxicity of epoxomicin. These results show that the effects of HSP70 on modulating cell death are unidirectional, and highlight the importance of also targeting the pro-survival pathways induced by proteasome inhibition during cancer treatment.
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IN THIS ISSUE| 01 February 2014
HSR and proteasome inhibition
Online Issn: 1477-9137
Print Issn: 0021-9533
© 2014. Published by The Company of Biologists Ltd
J Cell Sci (2014) 127 (3): e0302.
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HSR and proteasome inhibition. J Cell Sci 1 February 2014; 127 (3): e0302. doi:
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