CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells

Wang, Haibo; Qian, Zhengyao; Zhao, Hui; Zhang, Xibo; Shu-qiang, Che; Zhang, Hongtao; Shang, Haitao; Bao, Jie; Liu, Junjian; Li, Zhong‐Lian

doi:10.3892/mmr.2015.3871

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…P-gp is the most common member of the ATP binding cassette (ABC) family of transporters. It is known that MDR also intervenes in the acquired resistance to sorafenib [ 34 ]. However, whether P-gp plays a role in the resistance to sorafenib in HCC urgently requires clarification.…”

Section: Discussionmentioning

confidence: 99%

Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells

et al. 2017

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Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial–mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.

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Section: Discussionmentioning

confidence: 99%

Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells

et al. 2017

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“…Yet, sorafenib treatment of HCC patients has a low response rate or only prolongs patient's life by months due to drug resistance (54, 56). Previous research shows that ABCB1 and ABCG2 mediates sorafenib resistance in HCC (57,58). In our study here, we validate that circulating GHRA inhibits the gene expression of ABCB1 and ABCG2 in the HCC tumors and markedly sensitizes tumors to sorafenib effect to the extent of complete remission in some of the experimental mice.…”

Section: Discussionsupporting

confidence: 82%

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“…Yet, sorafenib treatment of HCC patients has a low response rate or only prolongs patient’s life by months due to drug resistance ( 54 , 56 ). Previous research shows that ABCB1 and ABCG2 mediates sorafenib resistance in HCC ( 57 , 58 ). In our study here, we validate that circulating GHRA inhibits the gene expression of ABCB1 and ABCG2 in the HCC tumors and markedly sensitizes tumors to sorafenib effect to the extent of complete remission in some of the experimental mice.…”

Section: Discussionmentioning

confidence: 96%

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

et al. 2022

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Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

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CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells

Cited by 14 publications

References 24 publications

Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells

Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells

DataSheet_1.pdf

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

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