Downregulation of Hsp70 inhibits apoptosis induced by sialic acid-binding lectin (leczyme)

Abstract

Heat shock proteins (Hsps) are molecular chaperones that maintain homeostasis of organisms. In regards to the Hsps, many studies have investigated the structure, expression, localization and functions of Hsp70 and Hsc70 including expression in the glycosphingolipid-enriched microdomain (GEM) on the cell surface and involvement in cell death. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity. SBL has potential as a new type of anticancer drug, since it causes cancer-selective induction of apoptosis by multiple signaling pathways in which RNA is its target; and the participation of the mitochondrial pathway and the endoplasmic reticulum (ER) stress-mediated pathway has been suggested. It has also been suggested that receptor(s) for SBL (SBLR) may exist in the GEM on the cell surface. In the present study, we studied the possible involvement of Hsp70 and Hsc70 in SBL-induced apoptosis. We showed that Hsp70 and Hsc70 were expressed on the P388 cell surface similar to SBLR, and their distribution in cells dramatically changed immediately prior to the execution of apoptosis following stimulation of SBL. Functional study of Hsp70 revealed that decreased expression of Hsp70 diminished the apoptosis induced by SBL. It is suggested that Hsp70 participates in the antitumor effect of SBL.

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

“…Hsp70 can be associated with the co-chaperones Hsp40 and can also collaborate with Hsp90 in various cellular compartments [ 89 ]. Overexpression of Hsp70 can determine resistance against apoptosis-inducing agents while downregulation of Hsp70 levels leads to increased sensitivity towards these agents [ 90 , 91 ]. Hsp70 levels were increased in different type of tumours and its presence is associated with poor prognosis in breast and endometrial cancer.…”

The effects of icariin on the expression of HIF-1α, HSP-60 and HSP-70 in PC12 cells suffered from oxygen–glucose deprivation-induced injury

“…Down-regulation of HSP-70 reduces apoptosis (Tatsuta et al. 2014 ). Extracellular HSP-70 activates TLRs in the cell surface, and promotes an inflammatory response which exacerbates ischaemia injury (Asea et al.…”

Antitumor Potential of Marine and Freshwater Lectins

“…Just as in a jigsaw puzzle, many studies have tried to elucidate the proper molecular mechanism of action of SBLc. The pieces of the puzzles are a tumor-specific mechanism of action, the activation of the intrinsic apoptotic pathway with the involvement of heat shock protein 70 (HSP70) and the phosphorylation of p38 MAPK [108,110,116,120,134,135]. The role of the lectin part of SBLc is to select cancer cells through the binding of specific sialic acid carbohydrates residues; then, specific receptors allow it to penetrate the cells, where the RNAse activity promotes the cleavage of RNA.…”

“…On p388 mouse lymphoma cells, HSP70 was linked to its ability to cause apoptosis. Even though the mechanism through which HSP70 assists SBLc cytotoxicity is not clear, it does not involve the binding between SBLc and cell membrane [109,135]. Finally, even if mitochondrial disruption is often part of SBLc mechanism of action, this lectin promoted a caspase-independent modality of cell death in SK-Hep1 hepatocellular carcinoma cells [120].…”

“…Likewise, the ubiquitin proteasome system may be involved in HER2 downregulation [114]. The hypothesis is based on the observation that SBLc modulates HSP70 [109,135]. Indeed, HSP70, together with HSP90, is responsible for the delivery of proteins, such as HER, to the ubiquitin-proteasome system in order to be degraded [114].…”