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Yu Y.-L.,Graduate Institute of Cancer Biology And | Yu Y.-L.,Medical University and Hospital | Yu Y.-L.,Asia University, Taiwan | Yu S.-L.,Asia University, Taiwan | And 13 more authors.
Journal of Agricultural and Food Chemistry | Year: 2010

Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O6-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs. © 2009 American Chemical Society O6-Methylguanine methyltransferase (MGMT), synergistic effect, 1, 3-bis(2-chloroethyl)1-nitrosourea (BCNU), methylation-specific PCR.

Luo J.,University of Rochester | Lee S.O.,University of Rochester | Cui Y.,University of Rochester | Yang R.,University of Rochester | And 4 more authors.
Oncotarget | Year: 2015

Several infiltrating cells in the tumor microenvironment could influence the cancer progression via secreting various cytokines. Here, we found the CCL5 secreted from BM-MSCs suppressed androgen receptor (AR) signals via enhancing the expression of hypoxia inducible factor 2a (HIF2a) in prostate cancer (PCa) cells. Mechanism dissection revealed that the increased HIF2a might alter the AR-HSP90 interaction to suppress the AR transactivation, and inhibition of HIF2a reversed the BM-MSCs-increased PCa stem cell population and PCa cells invasion. Importantly, CCL5 could suppress the prolyl hydroxylases (PHDs) expression, which might then lead to suppress VHL-mediated HIF2a ubiquitination. Together, these results demonstrated that the CCL5 signals from infiltrating BM-MSC cells to HIF2a signals within PCa cells might play a key role to increase PCa stem cell population and PCa metastasis via altering the AR signals. Targeting this newly identified CCL5/HIF2a/AR axis signal axis may allow us to develop a novel way to suppress PCa metastasis.

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