2011 Fiscal Year Final Research Report
Mechanism of multidrug resistance in mesothelioma cells, and the treatment strategy targeting CD44
| Project/Area Number |
21591003
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Tsutomu 順天堂大学, 医学部, 准教授 (40206503)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 悪性中皮腫 / 抗癌剤多剤耐性 / CD44 / オステオポンチン / ヒアルロン酸 |
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| Research Abstract |
Malignant pleural mesothelioma(MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin(OPN) and hyaluronate(HA), both of which are CD44 ligands, are highly detected in the pleural effusion and tissues of MPM, and suggested to be involved in the pathogenesis of MPM. However, the precise role of CD44, OPN, and HA, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants(ACC-MESO-1/OPN) of human mesothelioma cell line, which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced HA binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC. MESO. 1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC. MESO. 1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACC. MESO. 1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by chemotherapeutic drugs, such as NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA. Inhibition of interaction between CD44, OPN, and HA, may be one of the promising treatment strategy for patients with MPM.
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