Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia

Abstract

Imatinib is an effective therapy for chronic myeloid leukemia (CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-Abl. In this investigation, we studied an imatinib-resistant cell line (K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heatshock protein 70 (Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 (HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression (90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 lM of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinibresistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution.

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…Two recent frontiers in leukemia research are the emergence of imatinib-resistant CMLs [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] and the discovery of mutations at the Jak2 kinase in certain myeloproliferative diseases. These topic areas document the importance of genetic approaches in leukemia and abnormal hematopoiesis research as they were discovered upon identification of the genetic mutations responsible for the hematopoietic neoplasia.…”

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

“…The expression and action of heat shock protein 70 (Hsp70) in cancer cells vary among different types of cancers; in breast cancer, bladder cancer, and osteosarcoma, it constitutes a negative prognostic factor, whereas in esophageal cancer and renal cancer, it reportedly acts as a positive prognostic factor (Ciocca et al 2005;Uozaki et al 2000;Goloudina et al 2012). Since Pocaly et al (2007) first reported that Hsp70 expression is involved in imatinib resistance in chronic myeloid leukemia (CML), several other studies have also identified the involvement of Hsp70 expression in resistance to anticancer agents in other forms of cancer (Yang et al 2012;Behnsawy et al 2013).…”

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

“…However, these chaperones have been shown to contribute to cancer cell survival via multiple anti-apoptotic functions [6,9] and increased expression of Hsp70 has been implicated in resistance to cytotoxic chemotherapeutics [10,11]. Selective knockdown of Hsp70 by both RNAi and antisense results in cell arrest and death in a variety of cancer cell lines [12][13][14][15].…”