Pre-treatment with angiotensin-(1–7) inhibits tumor growth via autophagy by downregulating PI3K/Akt/mTOR signaling in human nasopharyngeal carcinoma xenografts

Lin, Yu-Tsai; Wang, Hung-Chen; Chuang, Hui-Ching; Hsu, Yi-Chiang; Yang, Ming-Yu; Chien, Chih-Yen

ABSTRACT: The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1–7) [Ang-(1–7)] is an endogenous heptapeptide hormone and important component of the renin–angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1–7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1–7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1–7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1–7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1–7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1–7) post-treatment. Taken together, these data indicate that Ang-(1–7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. KEY MESSAGES: Ang-(1–7) inhibits cell proliferation, migration, and invasion by activating autophagy. Ang-(1–7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway. Ang-(1–7) may provide a novel preventative treatment for NPC and recurrent NPC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00109-018-1704-z) contains supplementary material, which is available to authorized users.