Characterization of ADGRG6 as a potential molecular oncotarget of pancreatic cancer

Abstract Identifying novel therapeutic targets for pancreatic cancer (PC) is crucial for improving patient outcomes. This study identified the functions, expression, and associated mechanisms of adhesion G protein-coupled receptor G6 (ADGRG6/ GPR126) in PC. Bioinformatics analyses revealed substantial upregulation of ADGRG6 in human PC, correlating with poor survival rates and advanced tumor stages. Elevated ADGRG6 expression has been observed in human PC tissues and cell lines. Targeted depletion of ADGRG6 via the CRISPR/Cas9 knockout (KO) or lentiviral shRNA technology in established and primary PC cells (priPC-1) resulted in a substantial decrease in cell cycle progression, cell proliferation, viability, as well as reduced migratory and invasive capabilities. Conversely, ADGRG6 overexpression further enhanced the malignant behavior of PC cells. Mechanistically, ADGRG6 is crucial for Akt-mTOR cascade activation. ADGRG6 depletion markedly decreased Akt, S6, and 4E-BP1 phosphorylation. Constitutively active mutant Akt1 (S473D, caAkt1) reversed the anti-proliferative and anti-migratory effects of ADGRG65 shRNA and restored Akt-mTOR phosphorylation. Further analysis revealed that ADGRG6-driven Akt-mTOR activation is mediated by G protein inhibitory subunit 3 (Gαi3). ADGRG6 shRNA significantly inhibited subcutaneous PC xenograft growth in mice, accompanied by reduced Akt-mTOR signaling activation. In contrast, ADGRG6 overexpression promotes xenograft growth. Together, these findings establish ADGRG6 as a critical mediator of PC progression via Gαi3-dependent activation of the Akt-mTOR axis. Targeting ADGRG6 is a promising therapeutic strategy for combating PC.