Research Article: Modulation of Akt and ERK1/2 Pathways by Resveratrol in Chronic Myelogenous Leukemia (CML) Cells Results in the Downregulation of Hsp70

Date Published: January 14, 2010

Publisher: Public Library of Science

Author(s): Soumyajit Banerjee Mustafi, Prabir K. Chakraborty, Sanghamitra Raha, Matt Kaeberlein. http://doi.org/10.1371/journal.pone.0008719

Abstract: Resveratrol is known to downregulate the high endogenous level of Heat shock protein 70 (Hsp70) in Chronic Myelogenous Leukemia (CML) K562 cells and induce apoptosis. Since Heat Shock Factor 1 (HSF1) controls transcription of Hsp70, we wanted to probe the signaling pathways responsible for transcriptional activation of HSF1.

Partial Text: Cells are armed with various mechanisms which counteract stress to maintain cellular homoeostasis when challenged with subtle to acute changes in the physical, cellular or intracellular environment. Such a stress response helps the cell to evade apoptotic cell death and survive. Heat Shock Proteins (Hsps) are a family of stress proteins, both constitutive and inducible, primarily with chaperoning properties that help the cell to maintain cellular protein homeostasis and also to escape apoptosis under diverse forms of stress, from heat to alkalosis. In normal cells Hsp gene transcription is under the strict regulation of transcription factors belonging to the heat shock factor (HSF) family that ensure prompt switching on of transcriptional activity during stress and equally important post-stress switch off during recovery [1]. In cases where this co-ordination of HSF1 activation, stress response and post recovery deactivation mechanism is not well co-ordinated, the Hsps become highly overexpressed. This may render the cells anti-apoptotic and may eventually lead to malignancy. In fact a large number of malignancies have been linked to the overexpression of Hsps, in particular Hsp27, Hsp70 and Hsp90 [2].

Over the last few years Resveratrol have been the subject of extensive research which has elucidated the multifaceted role of this phytochemical from chemotherapeutic/chemopreventive potential to promoter of longevity [28]. The list of molecules targeted by Resveratrol is long and is being continuously updated. But the signaling pathways operative upstream of these final targets are often not well studied. We have previously established the efficacy of Resveratrol as a pro-apoptotic agent in K562 cells, essentially by virtue of its effect on the cellular chaperone Hsp70 [11]. As high endogenous levels of Hsp70 is a pathophysiological feature not only of CML but also of a large number of cancers [29], the downregulation of Hsp70 by Resveratrol in K562 serves as a very effective indicator of the chemotherapeutic potential of Resveratrol. This makes understanding of the signaling pathways modulated by Resveratrol for downregulating Hsp70 more relevant. Resveratrol has been shown to be able to induce apoptosis in Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines [30]. Exaggerated expression of Hsp70 is reported to be the most important protein responsible for Imatinib resistance in CML [15], [30]. There are some reports on the effect of Resveratrol on Akt and MAPK pathways, but the connections between these signaling pathways and Hsp70 have not been thoroughly explored. Resveratrol was found to modulate the function of HSF1 as a transcription factor for Hsp70 in K562 cells [11]. However the role of upstream kinases in controlling HSF1 activity was not properly delved into.

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http://doi.org/10.1371/journal.pone.0008719

 

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