Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth...

Area of Science:

• Endocrinology
• Cell Biology
• Oncology

Background:

• Somatostatin analogues (SSTA) are primary treatments for acromegaly, effectively reducing tumor size and normalizing growth hormone (GH) levels.
• A subset of patients exhibit resistance to SSTA, with underlying mechanisms requiring elucidation.
• The role of endoplasmic reticulum stress (ERS) and its intercellular transmission in SSTA resistance remains unexplored.

Purpose of the Study:

• To investigate the role of endoplasmic reticulum stress (ERS) in somatostatin analogue (SSTA) resistance in pituitary growth hormone (GH) adenoma.
• To explore the mechanisms of ERS induction and intercellular transmission in GH adenoma cells.
• To evaluate the potential of targeting ERS transmission to overcome SSTA resistance.

Main Methods:

• Primary GH adenoma cells and cell lines were treated with SSTA.
• ERS and autophagy signaling were assessed using techniques including LC3 adenovirus transfection, flow cytometry, western blotting, calcium imaging, and immunofluorescence.
• In vivo studies utilized xenograft and syngeneic tumor models to confirm ERS transmission effects.

Main Results:

• SSTA treatment was found to induce endoplasmic reticulum stress (ERS) in pituitary GH adenoma cells.
• ERS signals were observed to transmit intercellularly, correlating with reduced responsiveness to SSTA.
• SSTA stimulated inositol triphosphate (IP3) elevation, which mediated ERS intercellular transfer via connexin 36 channels.

Conclusions:

• Intercellular endoplasmic reticulum stress (ERS) transmission is a novel mechanism contributing to somatostatin analogue (SSTA) resistance in growth hormone (GH) adenoma.
• Targeting ERS intercellular transfer, potentially using connexin 36 blockers like Quinine, may enhance SSTA efficacy in treating GH adenoma.
• These findings offer insights for improving SSTA treatment strategies in acromegaly.