Activated CRH receptors inhibit autophagy by repressing conversion of LC3BI to LC3BII

Area of Science:

• Cell Biology
• Oncology
• Molecular Biology

Background:

• Microtubules-associated protein 1 light chain 3-B (LC3B) expression inversely correlates with breast cancer patient survival.
• Corticotropin-releasing hormone family (CRHs) signaling, mediated by CRH receptors (CRHRs), inhibits breast cancer cell migration.

Purpose of the Study:

• To investigate the role of CRHR1 and CRHR2 activation in regulating autophagy and breast cancer cell migration.
• To elucidate the signaling pathways linking CRHRs, autophagy, and cell invasion.

Main Methods:

• Utilized RT-4 and Hela cell lines with stable expression of RFP-GFP-LC3B.
• Employed lentiviral short hairpin RNA for stable CRHR1 silencing.
• Administered CRHRs agonists and antagonists, and Earle's Balanced Salt Solution (EBSS).
• Assessed LC3B conversion (LC3BI to LC3BII), autophagosome formation, and paxillin expression.

Main Results:

• CRHR1 and CRHR2 activation significantly reduced LC3BI to LC3BII conversion, inhibiting autophagy.
• CRHRs activation decreased autophagosome formation, linked to Phospholipase C β (PLCβ)-Inositol triphosphate (IP3)-mTOR signaling.
• CRHRs ligands restored paxillin expression, suppressed by EBSS, leading to reduced cell migration.

Conclusions:

• CRHRs signaling directly represses autophagy by inhibiting LC3B conversion.
• The CRHRs-autophagy axis influences cell adhesion molecule expression and suppresses breast cancer cell migration.
• This study reveals a novel CRHRs-autophagy connection, suggesting therapeutic potential for targeting cancer cell invasion.