BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation
- 14 October 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Angiogenesis
- Vol. 20 (1), 55-71
- https://doi.org/10.1007/s10456-016-9528-3
Abstract
Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.Keywords
Funding Information
- Department of Biotechnology , Ministry of Science and Technology (6242-P37/RGCB/PMD/DBT/PBKR/2015)
- University Grants Commission (F.No.41-507/2012 (SR))
- Vision Group of Science and Technology (VGST/ GRD231/ CISEE/2013-14, VGST/CISEE/ 2012-13/2882)
- Lady Tata Memorial Trust (IN) (JRS/2014-15/LTMT dated 11-08-2014)
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