Podocalyxin promotes cisplatin chemoresistance in osteosarcoma cells through phosphatidylinositide 3-kinase signaling.

Abstract

Osteosarcoma (OS) is the most common type of primary bone malignancy. The use of multiagent, intensive chemotherapy has markedly improved the long‑term survival rate of patients with OS. However, chemoresistance continues to be the principal reason for poor survival and disease recurrence in patients with OS. Innate or acquired resistance to cisplatin, which is one of the most effective drugs against OS, is common. Understanding the molecular basis underlying cisplatin chemoresistance in OS cells may serve as a basis for the identification of novel therapeutic targets and biomarkers. High expression levels of podocalyxin (PCX) have been shown to be correlated with poor outcome in various types of cancer. A recent study suggested that PCX may contribute to cancer chemoresistance. The present study aimed to explore the role of PCX in OS by determining its effects on cisplatin chemoresistance in OS cells. Stable overexpression and knockdown of PCX were performed in MG‑63 and U2OS human OS cell lines. Overexpression of PCX in the two cell lines significantly increased the half maximal inhibitory concentration (IC50) of cisplatin, cell colony formation, phosphatidylinositide 3‑kinase (PI3K) activity and Akt phosphorylation at serine 473, and decreased cisplatin‑induced cell apoptosis. Furthermore, the effects of PCX were largely attenuated by treatment with the selective PI3K inhibitor BKM120. Conversely, knockdown of PCX expression markedly decreased the IC50 of cisplatin, cell colony formation, PI3K activity and Akt phosphorylation at serine 473, and increased cisplatin‑induced cell apoptosis. In conclusion, the present study was the first, to the best of our knowledge, to provide evidence that PCX promotes cisplatin chemoresistance in OS cells through a PI3K‑dependent mechanism. The results of the present study provided novel insight not only into the functional role of PCX in cancer, but also into the molecular mechanisms underlying OS chemoresistance.

• Authors: Zheng Huang, Yanke Huang, Hongtao He, Jiangdong Ni
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 12 Issue 3 Pg. 3916-3922 (Sep 2015) ISSN: 1791-3004 [Electronic] Greece
• PMID: 26017117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Sialoglycoproteins
• podocalyxin
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bone Neoplasms (drug therapy)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression
• Humans
• Osteosarcoma (drug therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt (metabolism)
• Sialoglycoproteins (physiology)
• Signal Transduction