When phosphorylated by mitogen-activated protein kinases (MAPKs), including ERK, SAPK/JNK, and p38 MAPK, it regulates the transcription of a plethora of genes, including those involved in apoptosis, cell growth, proliferation, and the DNA damage response (DDR). Mutant p53 seems to overwrite the tumor suppressor function of ATF2.ĪTF2, as a transcription factor of the leucine zipper family, behaves as a tumor suppressor or as an oncogene in a context- and stimulus-dependent manner. ATF2-negative cells are highly resistant due to effective ATR/Chk1 DNA damage repair. We demonstrated a novel ATF2 scaffold function involved in the DDR pathway. Indeed, in silico modelling showed reduced ATR-Chk1 binding when ATF2 was docked into the complex. Co-immunoprecipitation and proximity ligation assays revealed that upon 5-FU treatment, ATF2 binds to ATR to prevent Chk1 phosphorylation. In ATF2-silenced HCT116 p53 −/− cells, 5-FU did not activate the DDR pathway. There were contradictory findings in HT29 ATF2-KO cells upon 5-FU exposure with low p-Chk1 Ser317 levels, strong apoptosis induction, but no effects on DNA damage. Chk1 inhibitor studies causally displayed the link between DDR and drug resistance. We observed that loss of ATF2 triggered dose- and time-dependent 5-FU resistance in HCT116 cells by activating the DNA damage response (DDR) pathway with high p-ATR Thr1989 and p-Chk1 Ser317 levels accompanied by an increase in the DNA damage marker γ-H2AX in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. Methods/Resultsįor our study, we had available HCT116 cells (wild-type p53) and HT29 colon tumor cells (mutant p53) and their corresponding CRISPR‒Cas9-generated ATF2-KO clones. To date, the role of ATF2 in the 5-FU response remains elusive. 5-Fluorouracil (5-FU) is the best-known chemotherapeutic drug for CC, but drug resistance affects its curative effect. Recently, we reported that low ATF2 expression is characteristic of highly invasive tumors, suggesting that ATF2 might also be involved in therapy resistance. The role of ATF2 in colon cancer (CC) is controversial.
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