Abstract
CD44 and CD147 are associated with cancer metastasis and progression. Our purpose in the study was to investigate the effects of down-regulation of CD44 or CD147 on the metastatic ability of prostate cancer (CaP) cells, their docetaxel (DTX) responsiveness and potential mechanisms involved in vitro and in vivo. CD44 and CD147 were knocked down (KD) in PC-3M-luc CaP cells using short hairpin RNA (shRNA). Expression of CD44, CD147, MRP2 (multi-drug resistance protein-2) and MCT4 (monocarboxylate tranporter-4) was evaluated using immunofluorescence and Western blotting. The DTX dose-response and proliferation was measured by MTT and colony assays, respectively. The invasive potential was assessed using a matrigel chamber assay. Signal transduction proteins in PI3K/Akt and MAPK/Erk pathways were assessed by Western blotting. An in vivo subcutaneous (s.c.) xenograft model was established to assess CaP tumorigenecity, lymph node metastases and DTX response. Our results indicated that KD of CD44 or CD147 decreased MCT4 and MRP2 expression, reduced CaP proliferation and invasive potential and enhanced DTX sensitivity; and KD of CD44 or CD147 down-regulated p-Akt and p-Erk, the main signal modulators associated with cell growth and survival. In vivo, CD44 or CD147-KD PC-3M-luc xenografts displayed suppressed tumor growth with increased DTX responsiveness compared to control xenografts. Both CD44 and CD147 enhance metastatic capacity and chemoresistance of CaP cells, potentially mediated by activation of the PI3K and MAPK pathways. Selective targeting of CD44/CD147 alone or combined with DTX may limit CaP metastasis and increase chemosensitivity, with promise for future CaP treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Basigin / biosynthesis*
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Basigin / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Docetaxel
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Hyaluronan Receptors / biosynthesis*
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Hyaluronan Receptors / genetics
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Monocarboxylic Acid Transporters / genetics
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Monocarboxylic Acid Transporters / metabolism
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / biosynthesis
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Multidrug Resistance-Associated Proteins / genetics
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Neoplasm Metastasis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasm Transplantation
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / mortality
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Taxoids / pharmacology*
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Transplantation, Heterologous
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Xenograft Model Antitumor Assays
Substances
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ABCC2 protein, human
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Antineoplastic Agents
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BSG protein, human
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CD44 protein, human
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Hyaluronan Receptors
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Monocarboxylic Acid Transporters
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Muscle Proteins
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Neoplasm Proteins
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SLC16A4 protein, human
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Taxoids
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Basigin
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Docetaxel
Grants and funding
This work was supported by National Health & Medical Research Council (NH&MRC) (YL), St George Medical Research Foundation (YL), Urology Research Fund (PJC) and St George Hospital Trust Fund (PHG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.