Emodin Suppresses Migration and Invasion through the Modulation of CXCR4 Expression in an Orthotopic Model of Human Hepatocellular Carcinoma

Abstract

Accumulating evidence(s) indicate that CXCL12-CXCR4 signaling cascade plays an important role in the process of invasion and metastasis that accounts for more than 80% of deaths in hepatocellular carcinoma (HCC) patients. Thus, identification of novel agents that can downregulate CXCR4 expression and its associated functions have a great potential in the treatment of metastatic HCC. In the present report, we investigated an anthraquinone derivative, emodin for its ability to affect CXCR4 expression as well as function in HCC cells. We observed that emodin downregulated the expression of CXCR4 in a dose-and time-dependent manner in HCC cells. Treatment with pharmacological proteasome and lysosomal inhibitors did not have substantial effect on emodin-induced decrease in CXCR4 expression. When investigated for the molecular mechanism(s), it was observed that the suppression of CXCR4 expression was due to downregulation of mRNA expression, inhibition of NF-κB activation, and abrogation of chromatin immunoprecipitation activity. Inhibition of CXCR4 expression by emodin further correlated with the suppression of CXCL12-induced migration and invasion in HCC cell lines. In addition, emodin treatment significantly suppressed metastasis to the lungs in an orthotopic HCC mice model and CXCR4 expression in tumor tissues. Overall, our results show that emodin exerts its anti-metastatic effect through the downregulation of CXCR4 expression and thus has the potential for the treatment of HCC.

Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer

“…In addition, emodin treatment significantly suppressed metastasis to the lungs in an orthotopic HCC mice model and CXCR4 expression in tumor tissues. Overall, our data also indicates that emodin exerts its anti-metastatic effect through the downregulation of CXCR4 expression and thus has the potential for the treatment of HCC [116].…”

Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

“…After 12 h, the insert was gently removed, creating a gap of ϳ500 m. The cells were treated with 5 M CIMO for 8 h before being exposed to 100 ng/ml CXCL12 for 24 h. The width of the wound was measured at time zero and after 24 h of incubation with and without CIMO in the absence or presence of CXCL12. Graphs were plotted against the percentage of migration distance the cells moved before and after treatment, normalized to control, as described previously (26).…”

Emodin induces hepatocellular carcinoma cell apoptosis through MAPK and PI3K/AKT signaling pathways in vitro and in vivo

“…In recent decades, increased attention was focused on anticancer activities of emodin since studies have reported that it exhibits antiproliferative and apoptosis-inducing effects in a number of human cancers such as colon, cervical and gastric cancer (9)(10)(11). It may also suppress migration and metastasis of cancer such as breast cancer and HCC (12,13). However, there is little information demonstrating the possible effects of emodin on the proliferation and apoptosis of HCC at present.…”