Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells

• Published in: Oncogene Vol. 29; no. 13; pp. 1941 - 1951
• Main Authors: Tajima, K, Ohashi, R, Sekido, Y, Hida, T, Nara, T, Hashimoto, M, Iwakami, S, Minakata, K, Yae, T, Takahashi, F, Saya, H, Takahashi, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2010; Nature Publishing Group
• Subjects: 631/45/127/1218; 631/67/1059/99; 692/699/67/1059/2326; 692/699/67/1641; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis; Binding sites; Cancer; Care and treatment; CD44 antigen; Cell Adhesion - drug effects; Cell Biology; Cell Line, Tumor; Cellular biology; Chemical properties; Chemoresistance; Chemotherapy; Development and progression; Diagnosis; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Etoposide - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Human Genetics; Humans; Hyaluronic acid; Hyaluronic Acid - metabolism; Hyaluronic Acid - pharmacology; Internal Medicine; Isoforms; Medicine; Medicine & Public Health; Mesothelioma; Mesothelioma - metabolism; Mesothelioma - pathology; Multidrug resistance; Multidrug resistant organisms; Oncology; original-article; Osteopontin; Osteopontin - metabolism; Phosphorylation; Pleural Neoplasms - metabolism; Pleural Neoplasms - pathology; Prognosis; Proteins; Risk factors; RNA, Small Interfering - pharmacology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; siRNA; Japan; multidrug resistance; mesothelioma; osteopontin; hyaluronan; CD44
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.478

Malignant pleural mesothelioma (MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin (OPN), a secreted noncollagenous and phosphoprotein, is suggested to be involved in the pathogenesis of MPM. However, the precise role of OPN, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants (ACC-MESO-1/OPN), 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 hyaluronate (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 NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA.