Oncogene database

3308

HSPA4

heat shock 70kDa protein 4;HSPA4;heat shock 70kDa protein 4

epididymis secretory sperm binding protein Li 5a|heat shock 70 kDa protein 4|heat shock 70-related protein APG-2|heat shock 70kD protein 4|heat shock protein, 110 kDa|hsp70 RY

5q31.1

protein-coding

Stress or heat shock proteins (HSPs) such as HSP27 and HSP70 are expressed in response to a wide variety of physiological and environmental insults including heat, reactive oxygen species or anticancer drugs. Their overexpression allows cells to survive to otherwise lethal conditions. Several different mechanisms may account for the cytoprotective activity of HSP27 and HSP70. First, both proteins are powerful chaperones. Second, both inhibit key effectors of the apoptotic machinery including the apoptosome, the caspase activation complex (both HSP27 and HSP70), and apoptosis inducing factor (only HSP70). Third, they both play a role in the proteasome-mediated degradation of apoptosis-regulatory proteins. HSP27 and HSP70 may participate in oncogenesis, as suggested by the fact that overexpression of heat shock proteins can increase the tumorigenic potential of tumor cells. The down-regulation or selective inhibition of HSP70 might constitute a valuable strategy for the treatment of cancer.

High levels of circulating heat shock protein 70 (HSP70) are detected in many cancers. In order to explore the effects of extracellular HSP70 on human microvascular endothelial cells (HMEC), we initially used gap-FRAP technique. Extracellular human HSP70 (rhHSP70), but not rhHSP27, blocks the gap-junction intercellular communication (GJIC) between HMEC, disrupts the structural integrity of HMEC junction plaques, and decreases connexin43 (Cx43) expression, which correlates with the phosphorylation of Cx43 serine residues. Further exploration of these effects identified a rapid transactivation of the Epidermal Growth Factor Receptor in a Toll-Like Receptor 4-dependent manner, preceding its internalization. In turn, cytosolic Ca2+ oscillations are generated. Both GJIC blockade and Ca2+ mobilization partially depend on ATP release through Cx43 and pannexin (Panx-1) channels, as demonstrated by blocking activity or expression of channels, and inactivating extracellular ATP. By monitoring dye-spreading into adjacent cells, we show that HSP70 released from human monocytes in response to macrophage colony-stimulating factor, prevents the formation of GJIC between monocytes and HMEC. Therapeutic manipulation of this pathway could be of interest in inflammatory and tumor growth.

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.

BACKGROUND: tumor progression in renal cell carcinoma (RCC) can be explained by a multistep model, in which the activation of certain oncogenes such as c-neu and c-fos appear to be early events in tumorigenesis, while the expression of p53 and pan-ras are found in advanced stages. MATERIAL AND METHODS: The expression of oncogenes and growth factors was examined in 29 primary tumor cell cultures (PTCC) of RCC using immunocytochemistry. RESULTS: In PTCC high expression of c-neu and c-fos was present in ALL tumors, whereas mdr, TGF-alpha, EGF, c-myc, pan-ras, p53 and HSP-70 was detected at low expression levels. In 27% (8/29) of PTCC, cell lines (CL) were established. oncogene expression was increased in CL compared to PTCC. CONCLUSION: The pattern of oncogene expressions found in CL is similar to findings described in highly malignant tumors in vivo. Therefore, the establishment of CL seems to depend on a selective recruitment of tumor cells with an upregulated oncogene expression.