Proteasome inhibitors differentially affect heat shock protein response in cancer cells.
The heat shock proteins (HSPs) are molecular chaperones that are emerging as biochemical regulators of cell growth, apoptosis, protein homeostasis and intracellular targeting of peptides. The immunological function of the HSPs are imparted by tissue specific peptides associated with the HSPs and as such autologous cancer derived HSP-peptide complexes are unique therapeutic agents. Since a majority of the intracellular peptides are generated by the proteasome, we examined the consequence of abrogation of proteasome function by proteasome inhibitors (PIs) such as Lactacystin, MG-132 and LLM on the growth and induction profile of HSP70 and gp96 using hematopoietic, lymphoid, and epithelial derived cancer cell lines. The effect on growth was measured by the XTT assay and induction of the heat shock proteins by western blot analyses using HSP70 and gp96 specific antibodies. Of the PIs tested, cancer cells, were most sensitive to MG-132 and least sensitive to LLM. MG-132 also showed a 10-fold differential sensitivity between estrogen receptor positive, (ER+) MCF-7 cells and negative cells, (ER-) MDA-MB-231. Induction of heat shock proteins, gp96 and HSP70 was, however, noted in response to LLM. Since LLM exhibited minimal cytotoxic effect, metabolic stress that results in induction of HSPs may not be translated in cell growth inhibition and that there may exist a cell-type specific phenomenon in the HSP response to PI mediated metabolic stress.
Ashok
B T
BT
Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Kim
E
E
Mittelman
A
A
Tiwari
R K
RK
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006360:Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015853:Cysteine Proteinase Inhibitors; D006360:Heat-Shock Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; C052646:sarcoma glycoprotein gp96 rejection antigens; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine