Proteasome inhibitors differentially affect heat shock protein response incancer cells

The heat shock proteins (HSPs) are molecular chaperones that are emerging a s biochemical regulators of cell growth, apoptosis, protein homeostasis and intracellular targeting of peptides. The immunological function of the HSP s 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 th e proteasome, we examined the consequence of abrogation of proteasome funct ion by proteasome inhibitors (PIs) such as Lactacystin, MG-132 and LLM on t he growth and induction profile of HSP70 and gp96 using hematopoietic, lymp hoid, and epithelial derived cancer cell lines. The effect on growth was me asured by the XTT assay and induction of the heat shock proteins by Western blot analyses using HSP70 and gp96 specific antibodies. Of the Pls 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 recept or positive, (ER+) MCF-7 cells and negative cells, (ER-) MDA-MB-231. Induct ion 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 inhibiti on and that there may exist a cell-type specific phenomenon in the HSP resp onse to PI mediated metabolic.