ATF5: development of oncogenic resistance to radiotherapy

irradiation and is a widely accepted therapeutic method for treating various types of cancers. However, a portion of cancer cells survives even after radiotherapy and leads to the development of recurrent tumors that gives rise to more malignant phenotypes than that before irradiation. We previously reported that any lung cancer cells that survive after irradiation have high invasiveness, which is regulated by several molecules, such as integrin β1 [1], myosin regulatory light chain (MRLC) [2], epidermal growth factor receptor [3], and filamin B [4]. These molecules play important roles in cell migration. However, the ability of lung cancer cells to survive irradiation and develop aggressive tumors after irradiation is poorly understood. We recently reported that activating transcription factor 5 (ATF5) leads to the development of radioresistance and malignant phenotypes in lung cancer cells after irradiation [5]. The two functions of ATF5 demonstrate " oncogenic resistance, " which implies that several molecules show enhanced resistance against some therapeutic techniques and simultaneously trigger cancer progression [6]. We hypothesize that ATF5 is one of the key molecules involved in development of oncogenic resistance to radiotherapy. First, we revealed that ATF5 enhances radioresistance in lung cancer cells. A549 human lung cancer cells that overexpress ATF5 shows higher survival ability after 10 Gy irradiation than that of the control A549 cells. Moreover, ATF5 expression and radioresistance of A549 cells varies depending on the cell cycle. During the G1-S phases of the cycle and not during the G2-M phases, A549 cells show high expression of ATF5 and radioresistance. We also demonstrated that ATF5 enhances radioresistance by promoting G1/S transition in the cell cycle. Thus, ATF5 plays an important role in radioresistance via regulation of the cell cycle in lung cancer cells. In addition, we found that ATF5 triggers lung cancer progression. ATF5 overexpression enhanced the proliferative and invasive abilities of A549 cells in in vitro cultures on a three-dimensional collagen gel. Furthermore, A549 cells overexpressing ATF5 showed high tumorigenic potential and development of invasive phenotypes in in vivo mouse experiments. In addition, ATF5 expression correlated with poor prognosis in lung Editorial cancer patients. We also investigated the molecules regulated by ATF5 and involved in development of the invasive capability of lung cancer cells. ATF5 promoted the expression of integrin β1, which is a key regulator of cell-matrix adhesion, and regulates A549 cell invasiveness. Moreover, ATF5 induced invasive phenotypes in A549 cells via prevention of the di-phosphorylation …