EIF4E regulates STEAP1 expression in peritoneal metastasis

Abstract

Gastric cancer is the most prominent form of malignancy in China, and the high mortality associated with it is mostly due to peritoneal metastasis. We have previously elucidated that the RNA-binding protein poly r(C) binding protein 1 (PCBP1) and miR-3978 function as repressors of peritoneal metastasis, partially by downregulation of six-transmembrane epithelial antigen of the prostate 1 (STEAP1). We now show that STEAP1 is regulated at the level of cap-dependent translation initiation by phosphorylated eIF4E. Chemically inhibiting phosphorylation of eIF4E or genetic ablation of phosphorylated eIF4E inhibit translational upregulation of STEAP1 in the peritoneal metastasis mimicking cell line MKN45 in comparison to the normal mesothelial cell line HMrSV5. Thus phosphorylation of eIF4E is required for peritoneal metastasis of gastric cancer via translational control of STEAP1. Chemical inhibitors targeting phosphorylation of eIF4E or its interaction with the translation initiation complex thus might prove effective in treating patients with peritoneal metastasis.

Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer

“…In addition, a STEAP1 CAR may be used against other STEAP1 positive cancers. 17 , 18 , 21 , 23 , 24 , 25 Here, we report the development of a CAR against STEAP1 and show that it has significant efficacy against prostate cancer cells in vitro and in vivo .…”

“… 22 In cancer forms where peritoneal metastases represent a key development, several studies have indicated that STEAP1 promotes tumor invasion into the peritoneum. 23 , 24 , 25 …”

Regulatory Roles of Six-Transmembrane Epithelial Antigen of the Prostate Family Members in the Occurrence and Development of Malignant Tumors

“…Gomes et al (2013) showed that 5α-dihydrotestosterone (DHT) or 17β-estradiol (E2) treatment of prostate cancer cells suppresses the expression of STEAP1, but that this down-regulation of STEAP1 is AR-dependent and ER-independent. In addition, up-regulated STEAP1 expression has also been observed in renal cell carcinoma, bladder cancer, Ewing's sarcoma, breast cancer, colorectal cancer (CRC), gastric cancer, ovarian cancer, and lung cancer (Maia et al, 2008;Azumi et al, 2010;Grunewald et al, 2012b;Zhuang et al, 2015;Wu et al, 2018;Nakamura et al, 2019;Guo Q. et al, 2020;Jiang et al, 2020;Jiao et al, 2020;Tian et al, 2020). Phosphorylated eIF4E is required for peritoneal metastasis of gastric cancer via initiating the cap-dependent translation of STEAP1, providing phosphorylation of eIF4E as an effective therapeutic target for patients with peritoneal metastasis through translational control of STEAP1 (Jiang et al, 2020).…”

“…In addition, up-regulated STEAP1 expression has also been observed in renal cell carcinoma, bladder cancer, Ewing's sarcoma, breast cancer, colorectal cancer (CRC), gastric cancer, ovarian cancer, and lung cancer (Maia et al, 2008;Azumi et al, 2010;Grunewald et al, 2012b;Zhuang et al, 2015;Wu et al, 2018;Nakamura et al, 2019;Guo Q. et al, 2020;Jiang et al, 2020;Jiao et al, 2020;Tian et al, 2020). Phosphorylated eIF4E is required for peritoneal metastasis of gastric cancer via initiating the cap-dependent translation of STEAP1, providing phosphorylation of eIF4E as an effective therapeutic target for patients with peritoneal metastasis through translational control of STEAP1 (Jiang et al, 2020). Importantly, high STEAP1 levels are associated with low overall survival (OS) rates of patients with prostate cancer, CRC, lung cancer, ovarian cancer, diffuse large B-cell lymphoma, acute myeloid leukemia and multiple myeloma (Moreaux et al, 2012;Ihlaseh-Catalano et al, 2013;Lee et al, 2016;Guo Q. et al, 2020;Jiao et al, 2020), suggesting the prognostic value of STEAP1 as a biomarker of cancer.…”

“…Oxidative stress and ROS levels are also suppressed in CRC cells, by STEAP1 silencing, through regulation of the nuclear erythroid 2-related factor (NRF2) transcription factor, resulting in reduced cell growth and elevated apoptosis (Nakamura et al, 2019). In gastric cancers, STEAP1 was shown to promote peritoneal metastasis, and up-regulation of STEAP1 was found to promote tumor proliferation, migration, invasion, and tumorigenicity (Wu et al, 2018;Jiang et al, 2020). Silencing of STEAP1 suppressed c-Myc expression in hepatocarcinoma to arrest cancer cells in G1 phase and inhibit cell proliferation (Iijima et al, 2021).…”