Oncogenic extracellular HSP70 disrupts the gap-junctional coupling between capillary cells

Area of Science:

• Cellular biology
• Immunology
• Biochemistry

Background:

• High levels of circulating heat shock protein 70 (HSP70) are observed in various cancers.
• Extracellular HSP70's role in cellular communication, particularly in endothelial cells, requires further investigation.

Purpose of the Study:

• To investigate the effects of extracellular heat shock protein 70 (HSP70) on human microvascular endothelial cells (HMEC).
• To elucidate the molecular mechanisms underlying HSP70-mediated disruption of intercellular communication.

Main Methods:

• Gap-FRAP (Fluorescence Recovery After Photobleaching) technique was employed to assess gap-junction intercellular communication (GJIC).
• Connexin43 (Cx43) expression and phosphorylation, Epidermal Growth Factor Receptor (EGFR) transactivation, and cytosolic Ca2+ oscillations were analyzed.
• The role of ATP release through Cx43 and pannexin-1 (Panx-1) channels was investigated.

Main Results:

• Extracellular human HSP70 (rhHSP70) blocked GJIC between HMEC, disrupted junctional plaque integrity, and decreased Cx43 expression and phosphorylation.
• EGFR transactivation via Toll-Like Receptor 4 (TLR4) preceded receptor internalization and led to cytosolic Ca2+ oscillations.
• GJIC blockade and Ca2+ mobilization were partially dependent on ATP release through Cx43 and Panx-1 channels.

Conclusions:

• Extracellular HSP70 disrupts HMEC communication by downregulating Cx43 and modulating calcium signaling through EGFR and TLR4.
• HSP70 released by monocytes can inhibit GJIC between monocytes and HMEC.
• Targeting this HSP70-mediated pathway holds potential for therapeutic interventions in inflammatory diseases and cancer growth.