Twist1-Mediated Adriamycin-Induced Epithelial-Mesenchymal Transition Relates to Multidrug Resistance and Invasive Potential in Breast Cancer Cells

Clinical Cancer Research - Tập 15 Số 8 - Trang 2657-2665 - 2009
Qingquan Li1, Jingda Xu1, Wenjuan Wang1, Xi-Xi Cao1, Qi Chen1, Feng Tang2, Zhongqing Chen2, Xiuping Liu1, Zu‐De Xu2
11Department of Pathology, Shanghai Medical College and
22Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

Tóm tắt

Abstract Purpose: Besides its therapeutic effects, chemotherapeutic agents also enhance the malignancy of treated cancers in clinical situations. Recently, epithelial-mesenchymal transition (EMT) has attracted attention in studies of tumor progression. We aimed to test whether transient Adriamycin treatment induces EMT and apoptosis simultaneously in cancer cells, clarify why the same type of cells responds differentially (i.e., apoptosis, EMT) to Adriamycin treatment, and elucidate the role of Twist1, the master regulator of EMT, in this process. Experimental Design: In unsynchronized MCF7 cells or cells synchronized at different phases, apoptosis, EMT, and concurrent events [multidrug resistance (MDR) and tumor invasion] after Adriamycin or/and Twist1 small interfering RNA treatment were examined in vitro and in vivo. The Adriamycin-induced Twist1 expression and the interaction of Twist1 with p53-Mdm2 were examined by immunoblotting and immunoprecipitation, respectively. Results: We showed in vitro that Adriamycin induced EMT and apoptosis simultaneously in a cell cycle–dependent manner. Only the cells undergoing EMT displayed enhanced invasion and MDR. Twist1 depletion completely blocked the mesenchymal transformation, partially reversed MDR, and greatly abolished invasion induced by Adriamycin. Also, we confirmed in vivo that Twist1 RNA interference improved the efficacy of Adriamycin for breast cancers. Further, Twist1 reduction in Adriamycin-treated cells promoted p53-dependent p21 induction and disrupted the association of p53 with Mdm2. Conclusions: Our studies show the diverse responses to Adriamycin treatment in cells at different phases, suggest an unrecognized role of EMT in regulating MDR and invasion, and show the efficacy of Twist1 RNA interference in Adriamycin-based chemotherapies for breast cancer.

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Tài liệu tham khảo

Kerbel RS. A cancer therapy resistant to resistance. Nature 1997;390:335–6.

Chaudhary PM, Roninson IB. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 1993;85:632–9.

Yang JM, Xu Z, Wu H, Zhu H, Wu X, Hait WN. Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. Mol Cancer Res 2003;1:420–7.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442–54.

Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 2004;48:365–75.

Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 2005;132:3151–61.

Moody SE, Perez D, Pan TC, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005;8:197–9.

Yang Y, Pan X, Lei W, et al. Regulation of transforming growth factor-β1-induced apoptosis and epithelial-to-mesenchymal transition by protein kinase A and signal transducers and activators of transcription 3. Cancer Res 2006;66:8617–24.

Yang J, Mani SA, Weinberg RA. Exploring a new Twist on tumor metastasis. Cancer Res 2006;66:4549–52.

Mironchik Y, Winnard PT, Jr., Vesuna F, et al. Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 2005;65:10801–9.

Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:1–11.

Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004;118:277–9.

Hoek K, Rimm DL, Williams KR, et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res 2004;64:5270–82.

Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117:927–39.

Kwok WK, Ling MT, Lee TW, et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 2005;65:5153–62.

Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 2003;4:657–65.

Wang X, Ling MT, Guan XY, et al. Identification of a novel function of TWIST, a bHLH protein, in the development of acquired Taxol resistance in human cancer cells. Oncogene 2004;23:474–82.

Okada H, Danoff TM, Kalluri R, et al. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 1997;273:563–74.

Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006;172:973–81.

Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131–42.

Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000;2:76–83.

Comijn J, Berx G, Vermassen P, et al. The two-handed e box binding zinc finger protein sip1 down-regulates e-cadherin and induces invasion. Mol Cell 2001;7:1267–78.

Carver EA, Jiang R, Lan Y, Oram KF, Gridley T. The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 2001;21:8184–8.

Yang JM, Medina GY, Vassil DJ, Liao AD, Hait J. Treatment of multidrug resistant (MDR1) murine leukemia with P-glycoprotein substrates accelerates the course of the disease. Biochem Biophys Res Commun 1999;266:167–73.

Yamauchi K, Yang M, Hayashi K, et al. Hoffman. Induction of cancer metastasis by cyclophosphamide pretreatment of host mice: an opposite effect of chemotherapy. Cancer Res 2008;68:516–20.

Kajiyama H, Shibata K, Terauchi M, et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol 2007;31:277–83.

Sherr Charles J. Cancer cell cycles. Science 1996;274:1672–7.

Kerbel RS, Waghorne C, Korczak B, Lagarde A, Breitman ML. Clonal dominance of primary tumours by metastatic cells: genetic analysis and biological implications. Cancer Surv 1988;7:597–629.

Kerbel RS, Korczak B, Lagarde A. Growth dominance of the metastatic cancer cell: cellular and molecular aspects. Adv Cancer Res 1990;5:87–132.

Su ZZ, Austin VN, Zimmer SG, Fisher PB. Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. Oncogene 1993;8:1211–9.

Li QQ, Wang WJ, Xu ZD, et al. Involvement of CD147 in regulation of multidrug resistance to P-gp substrate drugs and in vitro invasion in breast cancer cells. Cancer Sci 2007;98:1064–9.

Li QQ, Wang WJ, Xu ZD, et al. Up-regulation of CD147 and matrix metalloproteinase-2, -9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci 2007;98:1767–74.

Leptin M, Grunewald B. Cell shape changes during gastrulation in Drosophila. Development 1990;110:73–84.

Hosono S, Kajiyama H, Terauchi M, et al. Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients. Br J Cancer 2007;96:314–20.

Kwok WK, Ling MT, Lee TW, et al. Up-regulation of Twist in prostate cancer and its implication as a therapeutic target. Cancer Res 2005;65:5153–62.

Song LB, Liao WT, Mai HQ, et al. The clinical significance of Twist expression in nasopharyngeal carcinoma. Cancer Lett 2006;242:258–65.

Maestro R, Dei Tos AP, Hamamori Y, et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev 1999;13:2207–17.

Okorokov AL, Orlova EV, Kingsbury SR, et al. Molecular structure of human Geminin. Nat Struct Mol Biol 2004;11:1021–2.

Saito S'i, Yamaguchi H, Higashimoto Y, et al. Phosphorylation site interdependence of human p53 post-translational modifications in response to stress. J Biol Chem 2003;278:37536–44.

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Clinical Cancer Research

Tập 15 Số 8

2657-2665

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