Hypoxia pathway and hypoxia-mediated extensive extramedullary hematopoiesis are involved in ursolic acid’s anti-metastatic effect in 4T1 tumor bearing mice
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Jian-Li Gao1,2, Yan-Mei Shui1, Wei Jiang2, En-Yi Huang3, Qi-Yang Shou1, Xin Ji4, Bai-Cheng He3, Gui-Yuan Lv1, Tong-Chuan He2
1Zhejiang Chinese Medical University, Hangzhou, 310053, China
2Molecular Oncology Laboratory, The University of Chicago Medical Center, Chicago, IL 60637, USA
3Chongqing Medical University, Chongqing 400016, China
4School of Medicine, Zhejiang University, Hangzhou, 310058, China
Tong-Chuan He, email: [email protected]
Jian-Li Gao, email: [email protected]
Keywords: breast cancer, metastasis, hypoxic pathway, extensive extramedullary hematopoiesis, ursolic acid
Received: March 29, 2016 Accepted: September 24, 2016 Published: September 30, 2016
Hypoxic in the tumor mass is leading to the myeloproliferative-like disease (leukemoid reaction) and anemia of body, which characterized by strong extensive extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes essential for EMH processes including enhanced blood cell production and angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro. The suppression was mediated through the inhibition of multiple cell pathways linked to inflammation, proliferation, angiogenesis, and metastasis. UA also suppressed the leukemoid reaction and the EMH phenomenon of the tumor bearing mice without any significant suppression on body weight (i.p. by 20 mg/kg for 28 days). This is associated with the significant decrease in white blood cells (WBC), platelets (PLT) and spleen weight. During this process, we also detected the down-regulation of cell proliferative genes (PCNA, and β-catenin), and metastatic genes (VEGF, and HIF-1α), as well as the depression of nuclear protein intensity of HIF-1α. Furthermore, the expression of E2F1, p53 and MDM2 genes were increased in UA group when the VEGF and HIF-1α was over-expressed. Cancer cells were sensitive to UA treating after the silencing of HIF-1α and the response of Hypoxic pathway reporter to UA was suppressed when HIF-1α was over expressed. Overall, our results from experimental and predictive studies suggest that the anticancer activity of UA may be at least in part caused by suppressing the cancer hypoxia and hypoxia-mediated EMH.
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