MicroRNA profiles following telmisartan treatment in pancreatic ductal adenocarcinoma cells

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most devastating of all cancers with an extremely poor prognosis. It has few effective and reliable therapeutic strategies. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). Telmisartan inhibits cancer cell proliferation, but the underlying mechanisms in PDAC, remain unknown. Material and Methods: In the present study, we evaluated the effects of telmisartan on human PDAC cell proliferation in vitro. We assessed the effects of telmisartan on human PDAC cells using the cell lines PK-1 and PANC-1. Results: Telmisartan inhibited the proliferation of these cells via blockade of the G0 to G1 cell cycle transition. This was accompanied by a strong decrease in cyclin D1. Telmisartan was also shown by receptor tyrosine kinase and angiogenesis arrays to reduce the phosphorylation of epidermal growth factor receptor (EGFR), and miRNA expression was markedly altered by telmisartan in PK-1 cells. Conclusion: In conclusion, telmisartan inhibits human PDAC cell proliferation by inducing cell cycle arrest. Furthermore, telmisartan significantly altered miRNA expression in vitro. Taken together, our study demonstrated the therapeutic potential of telmisartan and provides molecular mechanistic insights into its anti-tumor effect on PDAC cells.

[1]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[2]  W. Blalock,et al.  MiRNA-210: A Current Overview. , 2017, Anticancer research.

[3]  T. Masaki,et al.  The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKa/mTOR pathway in vitro and in vivo , 2016, Oncotarget.

[4]  Yang Yang,et al.  MiR-210-3p inhibits the tumor growth and metastasis of bladder cancer via targeting fibroblast growth factor receptor-like 1. , 2017, American journal of cancer research.

[5]  S. Honda,et al.  Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T‐cell leukemia cells , 2016, FEBS open bio.

[6]  J. Kinoshita,et al.  The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer. , 2014, Cancer letters.

[7]  J. Gröne,et al.  Antiproliferative and apoptotic effects of telmisartan in human colon cancer cells , 2014, Oncology letters.

[8]  I. da Silva,et al.  Genetic Association Study of Angiotensin II Receptor Types 1 (A168G) and 2 (T1247G and A5235G) Polymorphisms in Breast Carcinoma among Brazilian Women , 2014, Breast Care.

[9]  T. Masaki,et al.  Targeting receptor tyrosine kinases in gastric cancer. , 2014, World journal of gastroenterology.

[10]  H. Narahara,et al.  Telmisartan Induces Growth Inhibition, DNA Double-Strand Breaks and Apoptosis in Human Endometrial Cancer Cells , 2014, PloS one.

[11]  J. Holmes,et al.  Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk. , 2014, Journal of the National Cancer Institute.

[12]  Yan-bin Zhao,et al.  Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer. , 2013, Cancer letters.

[13]  Yang Zhao,et al.  Angiotensin II receptor type 1 blockers suppress the cell proliferation effects of angiotensin II in breast cancer cells by inhibiting AT1R signaling. , 2012, Oncology reports.

[14]  K. Bhaskaran,et al.  Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database , 2012, BMJ : British Medical Journal.

[15]  Robert L. Sutherland,et al.  Cyclin D as a therapeutic target in cancer , 2011, Nature Reviews Cancer.

[16]  H. Kitagawa,et al.  Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells. , 2010, International journal of oncology.

[17]  D. Rowland,et al.  Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. , 2010, The Lancet. Oncology.

[18]  Quynh-Thu Le,et al.  Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer. , 2010, Translational oncology.

[19]  M. Moore,et al.  Advanced pancreatic carcinoma: current treatment and future challenges , 2010, Nature Reviews Clinical Oncology.

[20]  B. Gudjonsson.  Pancreatic cancer: survival, errors and evidence , 2009, European journal of gastroenterology & hepatology.

[21]  J. Kinoshita,et al.  Local angiotensin II-generation in human gastric cancer: correlation with tumor progression through the activation of ERK1/2, NF-kappaB and survivin. , 2009, International journal of oncology.

[22]  Y. Kawahito,et al.  Telmisartan as a peroxisome proliferator-activated receptor-γ ligand is a new target in the treatment of human renal cell carcinoma. , 2009, Molecular medicine reports.

[23]  G. Wakabayashi,et al.  Angiotensin II and epidermal growth factor receptor cross‐talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[24]  Y. Matsuda.  Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. , 2008, World journal of gastroenterology.

[25]  Y. Kawahito,et al.  Telmisartan is a potent target for prevention and treatment in human prostate cancer. , 2008, Oncology reports.

[26]  M. Saif,et al.  Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future. , 2007, JOP : Journal of the pancreas.

[27]  J. Herman,et al.  Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1 , 2006, Oncogene.

[28]  R. Schmid,et al.  Pancreatic cancer: basic and clinical aspects. , 2005, Gastroenterology.

[29]  Hidetaka Mochizuki,et al.  The Correlation Between Cytoplasmic Overexpression of Epidermal Growth Factor Receptor and Tumor Aggressiveness: Poor Prognosis in Patients With Pancreatic Ductal Adenocarcinoma , 2004, Pancreas.

[30]  Mitchell A. Avery,et al.  Identification of Telmisartan as a Unique Angiotensin II: Receptor Antagonist With Selective PPARγ–Modulating Activity , 2004, Hypertension.

[31]  Yoshiaki Miyauchi,et al.  Cyclins and cyclin‐dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis , 2003, Hepatology.

[32]  A. Miyajima,et al.  Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. , 2002, Cancer research.

[33]  Y. Sakamoto,et al.  Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. , 2001, Oncology reports.