Abstract
The major heat shock protein Hsp72 is expressed at high levels in various types of cancer. Here we attempt to clarify the role of Hsp72 in prostate cancer cells by studying the effects of specific downregulation of this protein using siRNA and antisense RNA approaches. Contrary to previous reports, specific depletion of Hsp72 did not reduce viability of the prostate carcinoma cell lines PC-3 and DU-145. However, even short-term downregulation of Hsp72 in these cells made them more sensitive to hyperthermia, inhibitors of proteasome and Hsp90, and tumor necrosis factor. Interestingly, prolonged downregulation of Hsp72 in PC-3 cells over 3 weeks aggravated these effects, as well as enhanced the sensitivity of cells to oxidative stress, radiation, cis-platinum, vinblastin and taxol. The increased sensitivity to the anticancer agents was due to increased apoptosis, as well as other types of cell death, which resulted in the loss of clonogenic survival. Prolonged downregulation of Hsp72 led to severe suppression of the major survival pathways, ERK and NF-κB, which may be responsible for enhanced sensitivity of prostate carcinoma cells to a variety of anticancer treatments, as well as reduction of the cell's capability of forming colonies in soft agar.
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Abbreviations
- ERK:
-
extracellular signal-regulated kinase
- Hsp:
-
heat shock protein
- JNK:
-
c-Jun N-terminal kinase
- MAP:
-
mitogen-activated kinase
- MTT:
-
3-[4, 5-dimethylthiasol-2-yl]-2,5-diphenyltetrasolium bromide
- NF-κB:
-
nuclear factor kappa B
- PARP:
-
poly(ADP-ribose) polymerase
- PDB:
-
phorbol dibutirate
- SiRNA:
-
small interfering RNA
- TNF:
-
tumor necrosis factor
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Acknowledgements
We thank Dr Jeng-Shin Lee for retroviral plasmids and Dr D Mosser for adenoviruses. The study was supported by NIH grant (to MS), by ACS grant IRG-72-001-29 (to VG) and the International Union Against Cancer Grant (to KB).
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Gabai, V., Budagova, K. & Sherman, M. Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene 24, 3328–3338 (2005). https://doi.org/10.1038/sj.onc.1208495
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DOI: https://doi.org/10.1038/sj.onc.1208495
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