Dehydrocostus Lactone Inhibits Proliferation, Antiapoptosis, and Invasion of Cervical Cancer Cells Through PI3K/Akt Signaling Pathway

Abstract

Melanoma is a tumor produced by skin melanocytes, which has a high metastatic rate and poor prognosis. So far, plenty of work has been done on melanoma, but mechanisms underlying melanoma development have not been fully elucidated. Here we identified regulator of G protein signaling 4(RGS4) as novel therapeutic target for malignant melanoma and its regulating effect on melanoma. We found that endogenous RGS4 expression was much lower in melanoma tissues and cells. In A375 cell line with low endogenous RGS4 expression, the function of RGS4 was detected by up-regulation its expression with pcDNA3.1-RGS4 and knockdown its expression with siRNA. Our results showed that RGS4 could significantly reduce the proliferation, migration and invasion of melanoma cells. RGS4 is an important regulator for the apoptosis of melanocyte, and the apoptosis rate is significantly decreased in low RGS4 enviroment. RGS4 induced non-activation of PI3K/AKT pathway, resulting in decreased expression of E2F1 and Cyclin D1, thus constraining cell proliferation and invasion. These results were further confirmed in M14 cell lines. Collectively, our findings show that RGS4 plays an important role in multiple cellular functions of melanoma development and is valuable to be a therapeutic target.

Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function

“…Dehydrocostus lactone (DL), a major sesquiterpene lactone compound extracted from Saussurea lappa, has been shown to possess multiple biologic activities, including antioxidant, anti-inflammatory, antiproliferative, anticancer, and apoptotic activities (23)(24)(25)(26)(27)(28)(29)(30). Although DL has been reported to protect osteoblastic MC3T3-E1 cells against oxidative stress and dysfunction (31)(32)(33), its role in osteoclast differentiation and function remains unknown.…”

Dehydrocostus Lactone Enhances Chemotherapeutic Potential of Doxorubicin in Lung Cancer by Inducing Cell Death and Limiting Metastasis

“…However, pAkt levels were effectively reduced at 1-μM DHC in both cell lines. DHC was also earlier reported to modulate Akt signaling in cervical cancer cells [ 24 ]. These observations indicate that DHC may act as anti-angiogenic agent in treatment conditions and it may also enhance the effects of DOX.…”

“…Tumor growth is critically regulated by Akt activation, which simultaneously causes activation of phosphorylation in a number of substrates, including GSK-3β [ 38 ], which regulates cell cycle progression by phosphorylating cyclin D1 [ 39 ]. DHC was reported to suppress proliferation and invasiveness of cervical cancer cells through downregulation of the I3K/Akt signaling pathway [ 24 ]. Our results are comparable to these observations that DHC inhibited the HIF-1α followed by inhibition of Akt/GSK-3β signaling pathways, leading to limiting the rate of metastasis in lung cancer cells.…”

“…The M-T staining of Matrigel plugs sections and the Hb content analysis confirms our observation. DHC was reported to suppress proliferation and invasiveness of cervical cancer cells [ 24 ] and suppressed proliferation, migration, and invasion of colorectal carcinoma [ 16 ]. Overall results demonstrate that DHC suppresses angiogenesis in a mouse model and enhances the anti-angiogenic properties of DOX when treated in combination.…”

“…DHC suppressed the angiogenesis of human umbilical vein endothelial cells (HUVEC) in vitro and in vivo through inhibition of Akt/glycogen synthase kinase (GSK-3β) and mechanistic target of rapamycin (mTOR) signaling pathways [ 23 ]. DHC was also shown to prevent invasiveness of cervical cancer cells through the PI3K/Akt signaling pathway [ 24 ] and inhibited invasion and migration in neuroblastoma cells [ 25 ]. These properties indicate that DHC might be a promising anti-tumor agent alone or in combination with other chemotherapeutic agents, and it may modulate tumor metastasis, which also needs validation.…”