Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cells survival via PI3-kinase/Akt pathway.
Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptor (AT1R) in some cancer. In this study, we examined the mechanisms by which Ang II affected the cell proliferation in AT1R-positive MCF-7 human breast cancer cells. Ang II stimulated the growth of breast cancer cells in a dose- and time-dependent manner. The maximal proliferation effect on MCF-7 cells was obtained with 10(-4) M Ang II at 24 h. Losartan (10(-5) M, an AT1R antagonist) significantly decreased the level of Ang-II-induced proliferative effects, whereas PD123319 (10(-5) M, an AT2R antagonist) had no effects. Moreover, Ang II could significantly accelerate S-phase progression, which was inhibited by losartan (10(-5) M) or LY294002 (50 microM, a PI3-kinase inhibitor). In addition, Ang II caused rapid activation of p-Akt in a dose- and time-dependent manner. 10(-4) M Ang II induced a significant increase of p-Akt in 15 min. The peak level of p-Akt could be persisted for at least 6 h. Among the signaling molecules downstream of Akt, we revealed that Ang II also significantly upregulated CyclinD1, GSK3beta, and downregulated p27. Pretreatment with losartan (10(-5) M) or LY294002 (50 microM) could significantly suppress these effects of Ang II. These findings suggest that Ang II plays a role in the growth of AT1R-positive breast cancer cells through PI3-kinase/Akt pathway activation. Therefore, targeting Ang II/AT1R signaling could be a novel therapeutic for breast cancer.
Zhao
Yanbin
Y
Medical Department of Breast Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China. zhaoyanbin1978@sina.com
Chen
Xuesong
X
Cai
Li
L
Yang
Yanmei
Y
Sui
Guangjie
G
Fu
Songbin
S
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D019808:Losartan