Hsp27 Protects Adenocarcinoma Cells from UV-Induced Apoptosis by Akt and p21-Dependent Pathways of Survival

Abstract

Transcriptional activation of p53 target genes, due to DNA damage, causes either apoptosis or survival by cell cycle arrest and DNA repair. However, the regulators of the choice between cell death and survival signaling have not been completely elucidated. Here, we report that human adenocarcinoma cells (MCF-7) survive UV-induced DNA damage by heat shock protein 27 (Hsp27)-assisted Akt/p21 phosphorylation/translocation. Protein levels of the p53 target genes, such as p21, Bcl-2, p38MAPK, and Akt, showed a positive correlation to Hsp27 level during 48 hours postirradiation, whereas p53 expression increased initially but started decreasing after 12 hours. Hsp27 prevented the G 1 -S phase cell cycle arrest, observed after 8 hours of post-UV irradiation, and PARP-1 cleavage was inhibited. Conversely, silencing Hsp27 enhanced G 1 -S arrest and cell death. Moreover, use of either Hsp27 or Akt small interference RNA reduced p21 phosphorylation and enhanced its retention in nuclei even after 48 hours postirradiation, resulting in enhanced cell death. Our results showed that Hsp27 expression and its direct chaperoning interaction increases Akt stability, and p21 phosphorylation and nuclear-to-cytoplasm translocation, both essential effects for the survival of UV-induced DNA-damaged cells. We conclude that the role of Hsp27 in cancer is not only for enhanced p53 proteolysis per se, rather it is also a critical determinant in p21 phosphorylation and translocation. Mol Cancer Res; 8(10); 1399-412. ©2010 AACR.

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

“…2, A and B), whereas Hsp27 showed a very slight increase from basal level and remained at the same level. These results are consistent with our previous report that wtp53 undergoes Hsp27-assisted proteasomal degradation in UV-induced DNA-damaged MCF-7 cells (40). Although wtp53 and mutp53 were indistinguishable by Western blotting because the antibody recognizes both, mutp53 is found to be very stable, unlike wtp53.…”

“…Also, HSF-1 homotrimer can bind to HSE in the MDR1 promoter region in competition with NF-B, to repress MDR1 gene expression (29). Hsp27, upon phosphorylation, interacts with p53 to enhance its degradation (40). In MCF-7/adr cells, HSF-1 and Hsp27 are inhibited, and p53 mutation is enforced.…”

“…1A). Because p53 is a ubiquitous protein, at normal conditions there will not be any wtp53 detectable (40). The detected p53 in MCF-7/adr cells has been characterized previously (21,22) as mutant p53 with the P72R point mutation and deletion of 126 -133 residues but with retention of the full C-terminal domain (nuclear localization signal) (22).…”

RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients

“…The binding of RP101 to HSPB1 had important functional consequences: interaction with Pro-CASP3, AKT1, and CYC1 was inhibited. HSPB1 acts as a switch between apoptosis and survival by modulating AKT1 stability (Kanagasabai et al 2010). Moreover, RP101 sensitized to heat shock and reduced tumor invasion in vitro.…”

Heat Shock Protein 27, a Novel Regulator of Transforming Growth Factor β Induced Resistance to Cisplatin in A549 Cell

“…The resistance to apoptosis was through the inhibition of caspase 9 and 3 activation, and this effect might be due to the increased expression of HSP27 [33]. Similar to cisplatin, UV is also known to induce the apoptosis in NSCLC cells, while the increased expression of HSP27 directed the chaperoning interaction with Akt and increased the stability of Akt, increased the phosphorylation of p21, and induced the resistance to UV-induced DNA damage and apoptosis in NSCLC cells [34]. Recent studies in MCF10A (human mammary epithelial cells) and HCT116 (human colon carcinoma cells) indicated that HSP27 regulates the stability of p53 and further modulates cellular senescence and apoptosis [35].…”