Prolyl-tRNA synthetase inhibition promotes cell death in SK-MEL-2 cells through GCN2-ATF4 pathway activation.

Takeo Arita, Megumi Morimoto, Yukiko Yamamoto, Hitoshi Miyashita, Satoshi Kitazawa, Takaharu Hirayama, Sou Sakamoto, Kazumasa Miyamoto, Ryutaro Adachi, Misa Iwatani, Takahito Hara

Biochemical and biophysical research communications 2017 Jul 08

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Protein translation is highly activated in cancer tissues through oncogenic mutations and amplifications, and this can support survival and aberrant proliferation. Therefore, blocking translation could be a promising way to block cancer progression. The process of charging a cognate amino acid to tRNA, a crucial step in protein synthesis, is mediated by tRNA synthetases such as prolyl tRNA synthetase (PRS). Interestingly, unlike pan-translation inhibitors, we demonstrated that a novel small molecule PRS inhibitor (T-3861174) induced cell death in several tumor cell lines including SK-MEL-2 without complete suppression of translation. Additionally, our findings indicated that T-3861174-induced cell death was caused by activation of the GCN2-ATF4 pathway. Furthermore, the PRS inhibitor exhibited significant anti-tumor activity in several xenograft models without severe body weight losses. These results indicate that PRS is a druggable target, and suggest that T-3861174 is a potential therapeutic agent for cancer therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Citation

Takeo Arita, Megumi Morimoto, Yukiko Yamamoto, Hitoshi Miyashita, Satoshi Kitazawa, Takaharu Hirayama, Sou Sakamoto, Kazumasa Miyamoto, Ryutaro Adachi, Misa Iwatani, Takahito Hara. Prolyl-tRNA synthetase inhibition promotes cell death in SK-MEL-2 cells through GCN2-ATF4 pathway activation. Biochemical and biophysical research communications. 2017 Jul 08;488(4):648-654