OR2T6 modulates autophagy through the PPP3CA-mediated pathways to suppress gastric cancer

The role of autophagy in gastric cancer (GC) progression remains elusive, warranting further investigation into its mechanisms and therapeutic implications. In this study, we demonstrate that olfactory receptor family 2 subfamily T member 6 (OR2T6) is downregulated and correlates with poorer prognosis in GC tissues. Functionally, OR2T6 induces autophagy initiation while blocking autophagic flux by compromising lysosomal function and inhibits cell proliferation both in vitro and in vivo. Mechanistically, co-immunoprecipitation (Co-IP) and mass spectrometry (MS) analyses reveal that OR2T6 specifically binds to PPP3CA. OR2T6 facilitates the protein stability and enzyme activity of PPP3CA through the ubiquitin-proteasome system and the promotion of calcium ion influx via the Gs/cAMP/PKA channel signaling axis. Our further research demonstrates that OR2T6 binds to PPP3CA, which suppresses the AKT/mTOR signaling pathway, thereby inhibiting tumor proliferation and promoting autophagy initiation. Interestingly, it facilitates the nuclear translocation of TFEB, a key regulator of lysosomal biogenesis, which leads to the transcriptional inactivation of lysosomal target genes (LAMP1, MCOLN1, ATP6V1H, CTSB, and CTSD), impairing lysosomal function and blocking autophagic flux. Collectively, we report that OR2T6 binds to and promotes PPP3CA, which subsequently initiates autophagy, inhibits proliferation by suppressing the AKT/mTOR pathway, and then blocks autophagic flux through TFEB-mediated lysosomal dysfunction. These findings suggest that OR2T6 may be a potential therapeutic target for GC.