Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation

Area of Science:

• Cellular signaling pathways
• Molecular mechanisms of apoptosis

Background:

• G-protein coupled receptors (GPCRs) regulate cell proliferation and differentiation.
• Previous work showed GnRH receptor (GnRHR) GqPCR signaling induces apoptosis in prostate cancer cells via reduced AKT activity and elevated JNK phosphorylation.
• The prevailing view was that GqPCRs primarily activate AKT, prompting an investigation into the generality and signaling of this phenomenon.

Purpose of the Study:

• To investigate the generality of G-protein coupled receptor (GPCR)-mediated apoptosis.
• To elucidate the specific signaling pathways involved in GPCR-induced apoptosis.
• To understand how GPCRs, particularly GnRH and PGF2α, induce apoptosis through protein kinase C (PKC) activation.

Main Methods:

• Screening of 21 cell lines to observe signaling component phosphorylation.
• Western blotting to analyze signaling pathways.
• Detailed study of SVOG-4O and αT3-1 cells to confirm Gq- and PKC-dependent apoptosis.

Main Results:

• PKC activation was found to reduce AKT activity and correlate with JNK activation and apoptosis across cell lines.
• PGF2α and GnRH agonist (GnRH-a) induced significant Gq- and PKC-dependent apoptosis in SVOG-4O and αT3-1 cells.
• Apoptosis signaling involved two branches downstream of PKC: c-Src activation of the JNK cascade and reduced AKT activity alleviating MLK3 inhibition, with MKK7 transmitting the signal upstream of JNK.

Conclusions:

• A general mechanism for G-protein coupled receptor (GPCR)-induced apoptosis was identified.
• This mechanism operates independently of death receptors.
• The findings are applicable to both physiological and cancer-related systems.