Loss of DUSP6 accelerates radiation-induced senescence in colon cancer cells through ERK1/2 hyperactivation

초록

Dual-specificity phosphatase 6 (DUSP6) plays a critical role in modulating the mitogen-activated protein kinase (MAPK) pathway, acting as a negative regulator of extracellular signal-regulated kinase 1/2 (ERK1/2) activity. In the context of cancer, dysregulation of MAPK signaling is often implicated in tumorigenesis and progression. We previously reported that long-term (>12 h) hypoxia promotes proteasomal degradation of DUSP6, which has a suppressive role in HIF-1α, and the loss of DUSP6 is involved in changes in the proliferative and migratory phenotype of human colon cancer cells. In this study, we investigated the impact of dusp6 loss on radiation-induced senescence. Using CRISPR/Cas9 technology, DUSP6 was selectively knocked out in CT26 mouse colon cancer cells, and the resulting cells were subjected to irradiation. Our findings demonstrated a pronounced increase in the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive senescent cells was markedly higher in DUSP6 KO cells treated with ionizing radiation (IR, 8 Gy) compared to wild type cells exposed to IR, suggesting that loss of DUSP6 enhances radiation-induced senescence in colon cancer cells. Furthermore, our investigation show that inhibition of ERK1/2 attenuates IR-induced p53 phosphorylation and p21 induction in DUSP6 KO colon cancer cells. Collectively, these results suggest that the loss of DUSP6 accelerates radiation-induced senescence through ERK1/2 activation, p53 phosphorylation, and p21 induction in colon cancer cells.