4.7 Article

Phosphorylation status of heat shock protein 27 plays a key role in gemcitabine-induced apoptosis of pancreatic cancer cells

Journal

CANCER LETTERS
Volume 313, Issue 2, Pages 218-225

Publisher

ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2011.09.008

Keywords

HSP27; Phosphorylation; Apoptosis; Gemcitabine; Pancreatic cancer

Categories

Funding

  1. Ministry of Education, Science, Sports and Culture of Japan [22790639]
  2. YOKOYAMA Foundation for Clinical Pharmacology
  3. Grants-in-Aid for Scientific Research [22790639] Funding Source: KAKEN

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Gemcitabine, an antitumor drug, is currently considered to be the standard of care for the treatment of advanced pancreatic cancer, but the clinical outcome is still not satisfactory. Although heat shock protein (HSP) 27 is implicated in the resistance to chemotherapy in several types of cancers, the precise role of phosphorylated HSP27 in cancer cells remains to be clarified. In this study, we investigated the relationship between the effect of gemcitabine and the phosphorylation status of HSP27 in pancreatic cancer cells, Panc1 and KP3. Gemcitabine suppressed pancreatic cancer cell growth and induced apoptosis. Gemcitabine caused activation of p38 mitogen-activated protein kinase (MAPK), MAPK-activated protein kinase 2 (MAPKAPK-2) and subsequently phosphorylation of HSP27 at Ser15, 78 and 82 without affecting total HSP27 levels. The inhibitions of p38 MAPK and MAPKAPK-2 reduced the phosphorylation of HSP27 and apoptosis in gemcitabine-treated cells. To further investigate the role of phosphorylated HSP27, we established Panc1 cell lines which were stably transfected with empty vector (empty cells), wild-type HSP27-encoding vector (WT cells) and 2 mutant HSP27-encoding vectors that mimic non-phosphorylated (3A), and phosphorylated (3D), respectively. In comparison of empty cells with WT cells, there was no difference in cell growth rate and the sensitivity to gemcitabine. Interestingly, cell growth of 3D cells was retarded as compared to that of 3A cells. Taken together, our results strongly suggest that phosphorylation status of HSP27 plays a key role in gemcitabine-induced growth suppression of pancreatic cancer. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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