Skip to main content
Top
Published in: Annals of Surgical Oncology 5/2009

01-05-2009 | ORIGINAL ARTICLE-TRANSLATIONAL RESEARCH AND BIOMARKERS

MDR1/P-gp and VEGF Synergistically Enhance the Invasion of Hep-2 Cells with Multidrug Resistance Induced by Taxol

Authors: Li Li, MD, PhD, Alice C. Jiang, BA, Pin Dong, MD, PhD, Haibo Wang, MD, Wei Xu, MD, PhD, Chengzhi Xu, MS

Published in: Annals of Surgical Oncology | Issue 5/2009

Login to get access

Abstract

Background

Tumor invasion/metastasis and multidrug resistance (MDR) are the main causes of treatment failure and high mortality in all kinds of cancer patients. The relationship between the two factors is still unclear. The aim of this study is to investigate the association between MDR and invasion, especially the role of multidrug resistance 1/P-glycoprotein (MDR1/P-gp) and vascular endothelial growth factor (VEGF) during the invasion.

Methods

Multidrug resistance 1 (MDR1) and VEGF receptor 2 (VEGFR-2) were detected with real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting at the levels of messenger RNA (mRNA) and protein, respectively. RNA interference was applied to inhibit the expression of MDR1. The invasive assays were performed with the CHEMICON cell invasion assay kit.

Results

The MDR cell line induced by Taxol (Hep-2T cell) was more invasive than its parent cell line (Hep-2 cell), which was at least in part mediated through the overexpressed MDR1/P-pg. MDR1-targeted RNA interference could effectively inhibit the expression of MDR1 and obviously decrease the invasive ability. Synergistic enhancing effects existed between MDR1/P-gp and VEGF on the invasion of Hep-2T cells. The expression of VEGFR-2 was elevated in Hep-2T cells. SU1498 could significantly decrease the invasion of Hep-2T cells. MDR1-targeted RNA interference and SU1498 had synergistic decreasing effect on the invasion of Hep-2T cells.

Conclusions

MDR1/P-pg may be a risk predictor for the invasion of laryngeal cancer. MDR1 knock down and VEGFR-2 inhibitor may be two promising treatment regiments for advanced laryngeal carcinoma patients with MDR and invasion/metastasis.
Literature
1.
go back to reference Liang Y, O’Driscoll L, McDonnell S, Doolan P, Oglesby I, Duffy K, et al. Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs. Int J Cancer. 2004;111:484–93.PubMedCrossRef Liang Y, O’Driscoll L, McDonnell S, Doolan P, Oglesby I, Duffy K, et al. Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs. Int J Cancer. 2004;111:484–93.PubMedCrossRef
2.
go back to reference Liang Y, McDonnell S, Clynes M. Examining the relationship between cancer invasion/metastasis and drug resistance. Curr Cancer Drug Targets. 2002;2:257–77.PubMedCrossRef Liang Y, McDonnell S, Clynes M. Examining the relationship between cancer invasion/metastasis and drug resistance. Curr Cancer Drug Targets. 2002;2:257–77.PubMedCrossRef
3.
go back to reference Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.PubMedCrossRef Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.PubMedCrossRef
4.
go back to reference DeClerck YA, Imren S, Montgomery AM, et al. Proteases and protease inhibitors in tumor progression. Adv Exp Med Biol. 1997;425:89–97.PubMed DeClerck YA, Imren S, Montgomery AM, et al. Proteases and protease inhibitors in tumor progression. Adv Exp Med Biol. 1997;425:89–97.PubMed
5.
go back to reference Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10:415–33.PubMedCrossRef Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10:415–33.PubMedCrossRef
6.
go back to reference Lamoreaux WJ, Fitzgerald ME, Reiner A, et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res. 1998;55:29–42.PubMedCrossRef Lamoreaux WJ, Fitzgerald ME, Reiner A, et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res. 1998;55:29–42.PubMedCrossRef
7.
go back to reference Liang Y, Meleady P, Cleary I, et al. Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness. Eur J Cancer. 2001;37:1041–52.PubMedCrossRef Liang Y, Meleady P, Cleary I, et al. Selection with melphalan or paclitaxel (Taxol) yields variants with different patterns of multidrug resistance, integrin expression and in vitro invasiveness. Eur J Cancer. 2001;37:1041–52.PubMedCrossRef
8.
go back to reference Osmak M, Niksic D, Brozovic A, et al. Drug resistant tumor cells have increased levels of tumor markers for invasion and metastasis. Anticancer Res. 1999;19:3193–7.PubMed Osmak M, Niksic D, Brozovic A, et al. Drug resistant tumor cells have increased levels of tumor markers for invasion and metastasis. Anticancer Res. 1999;19:3193–7.PubMed
9.
go back to reference Cillo C, Ling V, Hill RP. Drug resistance in KHT fibrosarcoma cell lines with different metastatic ability. Int J Cancer. 1989;43:107–11.PubMedCrossRef Cillo C, Ling V, Hill RP. Drug resistance in KHT fibrosarcoma cell lines with different metastatic ability. Int J Cancer. 1989;43:107–11.PubMedCrossRef
10.
go back to reference Cillo C, Dick JE, Ling V, et al. Generation of drug-resistant variants in metastatic B16 mouse melanoma cell lines. Cancer Res. 1987;47:2604–8.PubMed Cillo C, Dick JE, Ling V, et al. Generation of drug-resistant variants in metastatic B16 mouse melanoma cell lines. Cancer Res. 1987;47:2604–8.PubMed
11.
go back to reference Scotlandi K, Serra M, Nicoletti G, et al. Multidrug resistance and malignancy in human osteosarcoma. Cancer Res. 1996;56:2434–9.PubMed Scotlandi K, Serra M, Nicoletti G, et al. Multidrug resistance and malignancy in human osteosarcoma. Cancer Res. 1996;56:2434–9.PubMed
12.
go back to reference Vokes EE, Weichselbaum RR, Lippman SM, et al. Head and neck cancer. N Engl J Med. 1993;328:184–94.PubMedCrossRef Vokes EE, Weichselbaum RR, Lippman SM, et al. Head and neck cancer. N Engl J Med. 1993;328:184–94.PubMedCrossRef
13.
go back to reference O-charoenrat P, Modjtahedi H, Rhys-Evans P, et al. Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res. 2000;60:1121–8.PubMed O-charoenrat P, Modjtahedi H, Rhys-Evans P, et al. Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res. 2000;60:1121–8.PubMed
14.
go back to reference Li L, Jiang AC, Dong P, et al. The characteristics of Hep-2 cell with multiple drug resistance induced by Taxol. Otolaryngol Head Neck Surg. 2007;137:659–64.PubMedCrossRef Li L, Jiang AC, Dong P, et al. The characteristics of Hep-2 cell with multiple drug resistance induced by Taxol. Otolaryngol Head Neck Surg. 2007;137:659–64.PubMedCrossRef
15.
go back to reference Miletti-Gonzalez KE, Chen S, Muthukumaran N, et al. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 2005;65:6660–7.PubMedCrossRef Miletti-Gonzalez KE, Chen S, Muthukumaran N, et al. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 2005;65:6660–7.PubMedCrossRef
16.
go back to reference Wu H, Hait WN, Yang JM. Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res. 2003;63:1515–9.PubMed Wu H, Hait WN, Yang JM. Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res. 2003;63:1515–9.PubMed
17.
go back to reference Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.PubMedCrossRef Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.PubMedCrossRef
18.
go back to reference Boguslawski G, McGlynn PW, Harvey KA, et al. SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro. J Biol Chem. 2004;279:5716–24.PubMedCrossRef Boguslawski G, McGlynn PW, Harvey KA, et al. SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro. J Biol Chem. 2004;279:5716–24.PubMedCrossRef
20.
go back to reference Glisson BS, Murphy BA, Frenette G, et al. Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol. 2002;20:1593–9.PubMedCrossRef Glisson BS, Murphy BA, Frenette G, et al. Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol. 2002;20:1593–9.PubMedCrossRef
21.
go back to reference Morozevich GE, Kozlova NI, Preobrazhenskaya ME, et al. The role of beta1 integrin subfamily in anchorage-dependent apoptosis of breast carcinoma cells differing in multidrug resistance. Biochemistry (Mosc). 2006;71:489–95.CrossRef Morozevich GE, Kozlova NI, Preobrazhenskaya ME, et al. The role of beta1 integrin subfamily in anchorage-dependent apoptosis of breast carcinoma cells differing in multidrug resistance. Biochemistry (Mosc). 2006;71:489–95.CrossRef
22.
go back to reference Yang JM, Xu Z, Wu H, et al. Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. Mol Cancer Res. 2003;1:420–7.PubMed Yang JM, Xu Z, Wu H, et al. Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. Mol Cancer Res. 2003;1:420–7.PubMed
23.
go back to reference Weinstein RS, Jakate SM, Dominguez JM, et al. Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res. 1991;51:2720–6.PubMed Weinstein RS, Jakate SM, Dominguez JM, et al. Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res. 1991;51:2720–6.PubMed
24.
go back to reference Schneider J, Gonzalez-Roces S, Pollan M, et al. Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy. Breast Cancer Res. 2001;3:183–91.PubMedCrossRef Schneider J, Gonzalez-Roces S, Pollan M, et al. Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy. Breast Cancer Res. 2001;3:183–91.PubMedCrossRef
25.
go back to reference Yabushita H, Shimazu M, Noguchi M, et al. Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. Oncol Rep. 2003;10:89–95.PubMed Yabushita H, Shimazu M, Noguchi M, et al. Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. Oncol Rep. 2003;10:89–95.PubMed
26.
go back to reference Owen JL, Iragavarapu-Charyulu V, Gunja-Smith Z, et al. Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor. J Immunol. 2003;171:4340–51.PubMed Owen JL, Iragavarapu-Charyulu V, Gunja-Smith Z, et al. Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor. J Immunol. 2003;171:4340–51.PubMed
27.
28.
go back to reference Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13:9–22.PubMed Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13:9–22.PubMed
29.
go back to reference Wang Y, Kong W, Yue J, et al. Vascular endothelial growth factor165-regulated nasopharyngeal carcinoma cell lines invasion and migration involve expression and activation of matrix metalloproteinase-2. J Huazhong Univ Sci Technolog Med Sci. 2006;26:621–4.PubMedCrossRef Wang Y, Kong W, Yue J, et al. Vascular endothelial growth factor165-regulated nasopharyngeal carcinoma cell lines invasion and migration involve expression and activation of matrix metalloproteinase-2. J Huazhong Univ Sci Technolog Med Sci. 2006;26:621–4.PubMedCrossRef
30.
go back to reference Wang FQ, So J, Reierstad S, et al. Vascular endothelial growth factor-regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases. Int J Cancer. 2006;118:879–88.PubMedCrossRef Wang FQ, So J, Reierstad S, et al. Vascular endothelial growth factor-regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases. Int J Cancer. 2006;118:879–88.PubMedCrossRef
31.
go back to reference Sauter ER, Nesbit M, Watson JC, et al. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 1999;5:775–82.PubMed Sauter ER, Nesbit M, Watson JC, et al. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 1999;5:775–82.PubMed
32.
go back to reference Tao L, Zhou L, Zheng L, et al. Elemene displays anti-cancer ability on laryngeal cancer cells in vitro and in vivo. Cancer Chemother Pharmacol. 2006;58:24–34.PubMedCrossRef Tao L, Zhou L, Zheng L, et al. Elemene displays anti-cancer ability on laryngeal cancer cells in vitro and in vivo. Cancer Chemother Pharmacol. 2006;58:24–34.PubMedCrossRef
33.
go back to reference Fiedler W, Graeven U, Ergun S, et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood. 1997;89:1870–5.PubMed Fiedler W, Graeven U, Ergun S, et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood. 1997;89:1870–5.PubMed
34.
go back to reference Kyzas PA, Stefanou D, Batistatou A, et al. Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol. 2005;18:485–94.PubMedCrossRef Kyzas PA, Stefanou D, Batistatou A, et al. Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2. Mod Pathol. 2005;18:485–94.PubMedCrossRef
35.
go back to reference Klement G, Huang P, Mayer B, et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res. 2002;8:221–32.PubMed Klement G, Huang P, Mayer B, et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res. 2002;8:221–32.PubMed
Metadata
Title
MDR1/P-gp and VEGF Synergistically Enhance the Invasion of Hep-2 Cells with Multidrug Resistance Induced by Taxol
Authors
Li Li, MD, PhD
Alice C. Jiang, BA
Pin Dong, MD, PhD
Haibo Wang, MD
Wei Xu, MD, PhD
Chengzhi Xu, MS
Publication date
01-05-2009
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 5/2009
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0395-7

Other articles of this Issue 5/2009

Annals of Surgical Oncology 5/2009 Go to the issue