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

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 96; no. 12; pp. 1407 - 1418
• Main Authors: Lin, Yu-Tsai, Wang, Hung-Chen, Chuang, Hui-Ching, Hsu, Yi-Chiang, Yang, Ming-Yu, Chien, Chih-Yen
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2018; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Angiotensin; Angiotensin I - pharmacology; Angiotensin I - therapeutic use; Animals; Antitumor activity; Autophagy; Autophagy - drug effects; Bcl-2 protein; Biomedical and Life Sciences; Biomedicine; Cancer therapies; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Chemotherapy; Down-Regulation - drug effects; Human Genetics; Humans; Internal Medicine; Kinases; Male; Mice, Nude; Molecular Medicine; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Original; Original Article; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Radiation therapy; Renin; Signal transduction; Signal Transduction - drug effects; Throat cancer; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts; Nasopharyngeal carcinoma; Angiotensin-(1–7); Pre-treatment; Autophagy; PI3K/Akt/mTOR signaling
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-018-1704-z

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