Argonaute 2 modulates EGFR–RAS signaling to promote mutant HRAS and NRAS-driven malignancies

Abstract

Activating mutations in RAS GTPases drive nearly 30% of all human cancers. Our prior work described an essential role for Argonaute 2 (AGO2), of the RNA-induced silencing complex, in mutant KRAS-driven cancers. Here, we identified a novel endogenous interaction between AGO2 and RAS in both wild-type (WT) and mutant HRAS/NRAS cells. This interaction was regulated through EGFR-mediated phosphorylation of Y393-AGO2, and utilizing molecular dynamic simulation, we identified a conformational change in pY393-AGO2 protein structure leading to disruption of the RAS binding site. Knockdown of AGO2 led to a profound decrease in proliferation of mutant HRAS/NRAS-driven cell lines but not WT RAS cells. These cells demonstrated oncogene-induced senescence (OIS) as evidenced by beta-galactosidase staining and induction of multiple downstream senescence effectors. Mechanistically, we discovered that the senescent phenotype was mediated via induction of reactive oxygen species. Intriguingly, we further identified that loss of AGO2 promoted a novel feed forward pathway leading to inhibition of the PTP1B phosphatase and activation of EGFR-MAPK signaling, consequently resulting in OIS. Taken together, our study demonstrates that the EGFR-AGO2-RAS signaling axis is essential for maintaining mutant HRAS and NRAS-driven malignancies.

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…p53 was shown to be necessary for mitochondrial elongation in H-RAS-induced cellular senescence and in the replicative senescence of normal human cells [ 55 ]. Ras (mutant HRAS and NRAS)-induced senescence involved ROS and EGFR-argonaute 2 (AGO2) signaling in various human cancer cells, including HeLa, melanoma cells, and bladder cancer cells [ 56 ]. AGO2 bound to Ras and the loss of AGO2 inhibited cancer cell proliferation, senescence, and Ras signaling [ 56 ].…”

“…Ras (mutant HRAS and NRAS)-induced senescence involved ROS and EGFR-argonaute 2 (AGO2) signaling in various human cancer cells, including HeLa, melanoma cells, and bladder cancer cells [ 56 ]. AGO2 bound to Ras and the loss of AGO2 inhibited cancer cell proliferation, senescence, and Ras signaling [ 56 ]. Thus, targeting AGO2 could eliminate senescent cancer cells.…”