Expression of HSP27 results in increased sensitivity to tumor necrosis factor, etoposide, and H2O2 in an oxidative stress-resistant cell line

Abstract

The role of HSP27 in cell growth and resistance to stress was investigated using murine fibrosarcoma L929 cells (normally devoid of constitutively expressed small HSPs) and human osteoblast-like SaOS-2 cells stably transfected with a human hsp27 expression vector. Our data showed that our L929 cells were more resistant to oxidative stress than generally observed for this line. Production of HSP27 in these cells led to a marked decrease in growth rate associated with a series of phenotypical changes, including cell spreading, cellular and nuclear hypertrophy, development of an irregular outline, and a tremendous accumulation of actin stress fibers. By contrast, none of these changes was observable in SaOS-2/hsp27 transfectants overexpressing the protein product. Together, these observations are consistent with a cause-to-effect cascade relationship between increased (or induced) HSP27 expression, changes in cytoskeletal organization, and decreased growth. On the other hand, whereas the transfection of the hsp27 gene increased the cell resistance to heat in both cell lines, only in SaOS-2 cells was this associated with protection to the cytotoxic action of tumor necrosis factor-alpha (TNF-alpha) and etoposide. Unexpectedly, L929/hsp27 transfectants exhibited an increased sensitivity to both agents and also to H2O2. These data thus imply that different mechanisms are involved in the cell resistance to heat shock and to the cytotoxic action of TNF-alpha, etoposide, and H2O2. They also plead against the simple view that overexpression of a phosphorylatable HSP27 would necessarily be beneficial in terms of increased cell resistance to any type of stress. Our data further indicate that the role of HSP27 in cellular resistance to stress and in cell proliferation involves different targets and that the ultimate result of its interference with these processes depends on the intracellular context in which the protein is expressed.

Expression of Stress-related Genes in a Cadmium-resistant A549 Human Cell Line

“…Similarly, Trautinger et al (1997) found that overexpression of HSP27 in a stable transfected carcinoma cell line did not affect resistance to hydrogen peroxide. Similar results were reported by Mairesse et al (1998). It has been shown that HSP27 was involved in downregulation of proliferation of several human cell lines transfected with HSP27 gene (Kindas-Mugge et al, 1996Aldrian et al, 2002).…”

Overexpression of human 27 kDa heat shock protein in laryngeal cancer cells confers chemoresistance associated with cell growth delay

“…Another possible explanation for the relation between cell cycle delay and a cytoprotecitive eVect is that the synthesis of eVector molecules, if present, which mediate the apoptotic signal might also be aVected by a delay in the cell cycle, leading to an insuYcient execution of cell death program. However, the expression of HSP27 in L929 cells resulted in an increased sensitivity to TNF-, Etoposide, and H 2 O 2 even though HSP27 induces a growth delay in these cells (Mairesse et al 1998). These Wndings, along with the results reported herein, imply that growth inhibition induced by HSP27 cannot necessarily be extended to protection against to all the types of cellular stress.…”

“…The overexpression of HSP27 or its murine analogue, HSP25, has been shown to protect mammalian cells exposed to a variety of stress stimuli, including heat shock, oxidative stresses, and chemotherapeutic agents (Richards et al 1996;Fortin et al 2000) probably by inhibiting the mitochondrial pathway of apoptosis (Mairesse et al 1998;Bruey et al 2000). Furthermore, several studies have demonstrated that the expression of HSP27 is increased in various human cancers, suggesting that the cytoprotective activity of HSP27 might aVect tumorigenesis and the susceptibility of tumors to cancer treatment (Richards et al 1996;Vargas-Roig et al 1998;Fortin et al 2000).…”

p38 MAPK/HSP25 signaling mediates cadmium-induced contraction of mesangial cells and renal glomeruli

“…A number of studies report the association of HSP25 with actin. Overexpression of wild-type or mutant HSP25 that mimics phosphorylated HSP25 in cultured cells increased the amount of F-actin at the cell cortex and in stress fibers and enhanced the microfilament dynamics and cell motility (19,31,32,38). HSP25 fractionated with the membrane-associated actin cytoskeleton where dy- namic actin rearrangements occur continuously (43), and it formed bead-like structures (foci) that alternate with focal actin structures in the cortical submembrane region of Madin-Darby canine kidney cells (50).…”