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Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells
1Department of Respiratory Medicine, Juntendo University, School of Medicine, Bunkyo-Ku, Tokyo, Japan. tajiken@juntendo.ac.jp
Abstract:
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.
Insights
Osteopontin (OPN) enhances chemoresistance in malignant pleural mesothelioma (MPM) by promoting hyaluronate (HA) binding to CD44. This interaction activates Akt signaling, conferring multidrug resistance and hindering apoptosis in MPM cells.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignant pleural mesothelioma (MPM) exhibits resistance to chemotherapy, leading to poor patient outcomes.
- Osteopontin (OPN), a key phosphoprotein, is implicated in MPM pathogenesis, but its role in multidrug resistance is unclear.
Purpose of the Study:
- To investigate the specific role of OPN in conferring chemoresistance in MPM.
- To elucidate the molecular mechanisms underlying OPN-mediated multidrug resistance.
Main Methods:
- Established stable MPM cell transfectants overexpressing OPN (ACC-MESO-1/OPN).
- Assessed changes in hyaluronate (HA) binding and CD44 variant isoform expression.
- Investigated the impact of HA-CD44 interaction inhibition on chemoresistance and apoptosis.
- Analyzed Akt phosphorylation levels and the effect of its inhibition on apoptosis.
Main Results:
- OPN overexpression upregulated multidrug resistance in MPM cells via enhanced HA binding.
- CD44 variant isoforms inhibiting HA binding decreased in OPN-expressing cells.
- Inhibiting the HA-CD44 interaction abrogated chemoresistance and promoted apoptosis.
- OPN-induced chemoresistance involved Akt pathway activation, as evidenced by increased p-Akt levels.
Conclusions:
- OPN significantly contributes to multidrug resistance in MPM by enhancing CD44-HA binding.
- The HA-CD44 interaction activates pro-survival Akt signaling, protecting MPM cells from chemotherapy-induced apoptosis.
- Targeting the OPN-CD44-HA-Akt axis may represent a novel therapeutic strategy for overcoming chemoresistance in MPM.
