Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells

Feng, Yan; Wang, Xiaomin; Pan, Chao; Ma, Quan-Ming

doi:10.3748/wjg.15.1443

Cited by 18 publications

(11 citation statements)

References 26 publications

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“…5c). These observations are in agreement with earlier reports on multidrug-resistant hepatocellular carcinoma cells (22). In these cells, the drug resistance is mainly attributed to overexpression of P-gp, accompanied by downregulation of ERK1 and ERK2.…”

Section: Discussionsupporting

confidence: 83%

“…Traditionally, upregulation of MAPKs (JNK and p38) is associated with antimony-and arsenite-stimulated apop-tosis (15,(19)(20)(21). Interestingly, downregulation of a MAP kinase, ERK2, has also been reported in multidrug-resistant (MDR) hepatocellular carcinoma cells, suggesting that downregulation of ERK2 has a role in the toxicity pathway and resistance (22). Interestingly, MDR in cancer cells may be reversed by modulation of ERK activation, which induces apoptosis (23).…”

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confidence: 99%

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MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps

Garg

Goyal

2015

Antimicrob Agents Chemother

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Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) in the Indian subcontinent. Mitogen-activated protein kinases (MAPKs) are well-known mediators of signal transduction of eukaryotes, regulating important processes, like proliferation, differentiation, stress response, and apoptosis. In Leishmania, MAPK1 has been shown to be consistently downregulated in antimony-resistant field isolates, suggesting that it has a role in antimony resistance. The present work investigates the molecular mechanism of MAPK1 in antimony resistance in Leishmania donovani. The L. donovani MAPK1 (LdMAPK1) single-allele replacement mutants exhibited increased resistance to Sb(III) (5.57-fold) compared to wild-type promastigotes, while overexpressing parasites became much more susceptible to antimony. The LdMAPK1-mediated drug sensitivity was directly related to antimony-induced apoptotic death of the parasite, as was evidenced by a 4-to 5-fold decrease in cell death parameters in deletion mutants and a 2-to 3-fold increase in MAPK1-overexpressing cells. LdMAPK1-underexpressing parasites also exhibited increased P-glycoprotein (P-gp)-mediated efflux pump activity, while a significant decrease in pump activity was observed in overexpressing cells. This change in efflux pump activity was directly related to expression levels of P-gp in all cell lines. However, episomal complementation of the gene restored normal growth, drug sensitivity, P-gp expression, and efflux pump activity. The data indicate that LdMAPK1 negatively regulates the expression of P-glycoprotein-type efflux pumps in the parasite. The decrease in efflux pump activity with an increase in Ld-MAPK1 expression may result in increased antimony accumulation in the parasite, making it more vulnerable to the drug. L eishmania, a protozoan parasite, causes leishmaniasis, a group of diseases with clinical manifestations that range from selfhealing cutaneous and mucocutaneous skin ulcers to a fatal visceral form (visceral leishmaniasis [VL]). The disease imposes a significant burden of mortality and morbidity, affecting 12 million people in more than 88 countries in tropical and subtropical zones of the world (1). Since antileishmanial vaccines are still under development, control of the disease is dependent mostly on chemotherapy (2). However, the efficacy of Sb(V), the first-line treatment, is now threatened by the emergence of drug-resistant Leishmania parasites, as described in several regions of endemicity (3-5). During the last decade, several novel formulations of conventional antileishmanials, as well as new drugs, including the oral agent miltefosine, became available or were under investigation. However, their widespread use in poor countries is hindered by their high cost and also by concerns about toxicity and the emergence of resistance (6, 7). The present-day requirement in the treatment of leishmaniasis is to battle escalating lack of responsiveness to antimony, and hence, an urgent need exists...

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps

Garg

Goyal

2015

Antimicrob Agents Chemother

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“…It is known that ERK plays an important role in positively regulating expression of various MDR-related genes including MDR1, MRP1 and BMI1 (10)(11)(12)(13). A previous report showed that decreased activities of ERK1/2 was detected in Human leukemia U937 and HL60 cells overpressing Mda-7/IL-24 (4).…”

Section: Discussionmentioning

confidence: 99%

Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs

Zhao

Sun

et al. 2016

Oncology Reports

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Abstract. ) is a cytokine encoded by a tumor suppressor gene of the IL-10 family, also known as the melanoma differentiation associated gene-7 (Mda-7) and first discovered in human melanoma cells. Mda-7/IL-24 has been shown to inhibit the proliferation of various human tumor cell lines, but its effect on the sensitivity of B cell lymphoma to chemotherapy agents is not yet clear. The present study investigated the effects of Mda-7/IL-24 overexpression on the sensitivity of human B cell lymphoma cells to chemotherapy, as well as its mechanism of action. The sensitivity of stable Mda-7/IL-24 overexpressing Raji and Daudi cells to cis-diamminedichloroplatinum (CDDP), epirubicin and vinblastine (VCR) were assessed by the MTS method, and the IC 50 value calculated. Cell apoptosis and the intracellular accumulation of Rhodamine-123 were assayed by flow cytometry. The expression of multidrug resistance gene 1 (MDR1), B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1), topoisomerase II (Topo II) and multidrug resistance-related protein 1 (MRP1) mRNA and protein were analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. In addition, western blot analysis was also used to investigate the effect of Mda-7/IL-24 on activity of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells. Growth inhibition and apoptosis rates of Mda-7/IL-24 overexpressing Raji and Daudi cells were higher than those of non-transfected cells and cells transfected with vector alone when treated with CDDP, epirubicin and VCR. The IC 50 values of CDDP, epirubicin and VCR were lower for Mda-7/IL-24-overexpressing Raji and Daudi cells than for non-transfected cells and cells transfected with empty vector. Intracellular accumulation of Rhodamine-123 and the expression of Topo II were higher, while the levels of MDR1, BMI and MRP1 mRNA and protein were lower, in Mda-7/IL-24 overexpressing Raji and Daudi cells. Furthermore, the activities of GTP-RhoA-ERK signaling pathway in Raji and Daudi cells were suppressed. These results indicated that Mda-7/IL-24 enhanced the sensitivity of B lymphoma cells to chemotherapy agents by altering the expression of multidrug-resistance genes via downregulating GTP-RhoA-ERK signaling pathway, suggesting that treatment of B cell lymphomas with Mda-7/IL-24 could avoid MDR.

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“…The pore channel is opened following activation with ATP, and mediates the transport of several substrate molecules, including chemotherapeutic drugs, across extracellular and intracellular membranes ( 9 ). Previous studies have demonstrated that the expression of P-gp is significantly increased in multiple-drug-resistant HCC cells ( 10 , 11 ). The increased expression of P-gp facilitates the efflux of chemotherapeutic drugs out of cells, resulting in the increased drug resistance of HCC.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug-resistant human hepatocellular carcinoma cells to 5-FU

Tang

et al. 2015

Molecular Medicine Reports

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δ opioid receptor (DOR) was the first opioid receptor of the G protein-coupled receptor family to be cloned. Our previous studies demonstrated that DOR is involved in regulating the development and progression of human hepatocellular carcinoma (HCC), and is involved in the regulation of the processes of invasion and metastasis of HCC cells. However, whether DOR is involved in the development and progression of drug resistance in HCC has not been reported and requires further elucidation. The aim of the present study was to investigate the expression levels of DOR in the drug-resistant HCC BEL-7402/5-fluorouracil (BEL/FU) cell line, and its effects on drug resistance, in order to preliminarily elucidate the effects of DOR in HCC drug resistance. The results of the present study demonstrated that DOR was expressed at high levels in the BEL/FU cells, and the expression levels were higher, compared with those in normal liver cells. When the expression of DOR was silenced, the proliferation of the drug-resistant HCC cells were unaffected. However, when the cells were co-treated with a therapeutic dose of 5-FU, the proliferation rate of the BEL/FU cells was significantly inhibited, a large number of cells underwent apoptosis, cell cycle progression was arrested and changes in the expression levels of drug-resistant proteins were observed. Overall, the expression of DOR was upregulated in the drug-resistant HCC cells, and its functional status was closely associated with drug resistance in HCC. Therefore, DOR may become a recognized target molecule with important roles in the clinical treatment of drug-resistant HCC.

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Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells

Cited by 18 publications

References 26 publications

MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps

MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps

Mda-7/IL-24 enhances sensitivity of B cell lymphoma to chemotherapy drugs

Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug-resistant human hepatocellular carcinoma cells to 5-FU

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