The 70 kilodalton heat shock protein is an inhibitor of apoptosis in prostate cancer.
The 70 kD heat shock protein (HSP70) plays essential cellular roles in mediating intracellular protein folding and protecting cells from proteotoxic stress. This study has examined the role of HSP70 in the expression of apoptosis in prostate carcinoma cells. Apoptosis was negatively correlated with HSP70 expression in PC-3 cells heat shocked in vivo. Further experiments carried out on an in vitro reconstituted system with isolated nuclei and cytoplasm from PC-3 cells showed that purified HSP70 directly inhibits apoptosis in a dose-dependant manner. Therefore, the potential role of depletion of intracellular HSP70 was examined as a means of inducing apoptosis in PC-3 cancer cells. Depletion of HSP70 by two independent strategies, either with anti-sense oligonucleotides directed against HSP70 mRNA or with the bioflavinoid drug quercetin, led to apoptosis in the absence of stress. In addition, quercetin pre-treatment synergistically enhanced apoptosis in combination with heat shock. Thus, HSP70 plays a physiological role in tumour cells as an inhibitor of apoptosis occurring both spontaneously and after stress and is a potential target for apoptosis-based cancer therapy.
Jones
E L
EL
Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Zhao
M J
MJ
Stevenson
M A
MA
Calderwood
S K
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002474:Cell-Free System / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D016373:DNA, Antisense / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D011794:Quercetin / Q000494:pharmacology; D015843:Serpins / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014764:Viral Proteins / Q000494:pharmacology
D061945:Caspase Inhibitors; D016373:DNA, Antisense; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C064769:N-acetylsphingosine; D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D011794:Quercetin; D013110:Sphingosine