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

Abstract

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 (IC 50 ) 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 IC 50 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.

Silencing LPAATβ inhibits tumor growth of cisplatin-resistant human osteosarcoma in vivo and in vitro

“…As the most common primary malignancy of bone, osteosarcoma has complicated occurrence and development which have not been clarified yet. Although development of surgery combined with neoadjuvant chemotherapy has significantly improved, the survival rate of osteosarcoma in the last few decades has plateaued, which may be heavily influenced by resistance to chemotherapy drugs (16,17). Therefore, discovery of effective ways that can increase the sensitivity to chemotherapy will be important in antitumor effect.…”

Emerging Role of Podocalyxin in the Progression of Mature B-Cell Non-Hodgkin Lymphoma

“…Knockdown of PODXL in HCT15 colon carcinoma cells markedly increased the sensitivity to 5-fluorouracil, an inhibitor of thymidylate synthase, and to irinotecan [54], a topoisomerase I inhibitor with reported clinical activity against relapsed or refractory B-NHL in combination chemotherapy [115,116]. Furthermore, enforced expression and PODXL silencing studies in MG-63 and U2OS osteosarcoma cell lines showed that PODXL induces cisplatin chemoresistance via PI3K/AKT signaling pathway [88]. Cisplatin is a chemotherapeutic drug effective against many types of cancers, including NHL [117].…”

F‑box proteins involved in cancer‑associated drug resistance (Review)

“…Drug resistance can be classified into two main categories: intrinsic and acquired (2,3). To devise methods and drugs that can overcome the effects of drug resistance, researchers have been focusing on elucidating the molecular mechanisms underlying the development of drug resistance which can further help in elucidating chemoresistance-related mechanisms and devising methods of preventing it.…”