Kasumi-2

AGO2 Interaction is Essential for Mutant HRAS and NRAS-Driven Cell Proliferation

Activating mutations in RAS GTPases drive nearly 30% of human cancers. Siebenaler et al. investigated the interaction between AGO2 and RAS in both wild-type and mutant HRAS/NRAS cells, exploring its regulation and downstream effects on cell proliferation and senescence.

They assessed whether AGO2 functionally promotes mutant HRAS and NRAS cancers. Using two independent shRNAs targeting AGO2, they generated stable cell lines (T24, Kasumi-2, Mel-Juso, SK-MEL-2, H1299, HeLa, and A375) with mutant HRAS or NRAS. As expected, AGO2 knockdown significantly reduced cell proliferation in mutant HRAS-driven T24 and Kasumi-2 cells (Fig. 1A). Similarly, two mutant NRAS-driven melanoma cell lines (Mel-Juso and SK-MEL-2) showed marked growth reduction after AGO2 loss (Fig. 1B). This suggests AGO2 promotes oncogenic HRAS and NRAS proliferation in mutant RAS cells. Their previous work showed that KRAS-independent cell lines are resistant to AGO2 loss. Consistently, AGO2 knockdown in the WT RAS cell line HeLa did not affect cell proliferation (Fig. 1C). Similarly, the BRAF^V600E-mutant melanoma cell line A375, which has a constitutively active ERK/MAPK pathway independent of RAS, was also unaffected by AGO2 knockdown (Fig. 1C). Furthermore, overexpression of AGO2 enhanced mutant NrasG12D-driven transformation in NIH-3T3 cells, but did not affect BRAFV600E-driven transformation. These results indicate that AGO2's role in mutant RAS cells is not seen in constitutive MAPK-driven cancers, supporting the necessity of the AGO2-RAS interaction in mutant RAS cells.