ATF4 promotes lung cancer cell proliferation and invasion partially through regulating Wnt/β-catenin signaling

Activating transcription factor 4 (ATF4) is a member of the cAMP response element binding (CREB) protein family and has been reported to participate in cancer progression; however, its molecular mechanism is not fully understood. In this study, we investigated the function of ATF4 in non-small cell lung cancer and its molecular regulation. We detected cytoplasmic and nuclear ATF4 expression in lung cancer A549, H1299, and LK2 cells, and the total expression of ATF4 was higher than that in HBE cells (p < 0.05). Higher nuclear ATF4 expression was detected in all these cells compared to cytoplasmic ATF4 expression (p < 0.05). Overexpression of ATF4 in A549 cells significantly promoted cancer cell growth and invasion (p < 0.05). Expression of Wnt signaling molecules, including beta-catenin, MMP7, and cyclin Dl, and the activity of canonical Wnt signaling were also significantly promoted by ATF4 (p < 0.05). ICG001, a canonical Wnt signaling inhibitor that selectively inhibits beta-catenin/cyclic adenosine monophosphate response element binding protein (CBP) interaction, significantly inhibited cancer cell invasion and Wnt signaling. The function of ATF4 was also significantly inhibited by ICG001 (p < 0.05). However, compared to treatment with ICG001, the invasion ability of cancer cells treated with both ICG001 and ATF4 cDNA significantly increased (p < 0.05), which indicates that the function of ATF4 was not dependent only on Wnt/beta-catenin signaling. The function of ATF4 in the regulation of beta-catenin expression was not significantly affected by ICG001 (p > 0.05). The function of ATF4 to promote the activity of Wnt/beta-catenin signaling in cancer cells was abolished by treatment with ICG001 (p > 0.05). These results indicate that ATF4 may contribute to lung cancer progression at least partly by regulating Wnt/beta-catenin signaling.

Automated summary

The study found that ATF4 expression in non-small cell lung cancer is associated with cancer cell growth and invasion, and it participates in cancer progression by promoting the activity of the Wnt signaling pathway. ICG001 can inhibit the function of ATF4, but when ATF4 and ICG001 are combined, the invasion ability of cancer cells significantly increases, indicating that ATF4's function is not solely dependent on the Wnt/beta-catenin signaling pathway.