title: P53 is required for Doxorubicin-induced apoptosis via the TGF-beta signaling pathway in osteosarcoma-derived cells.
abstract: Osteosarcoma is the most common type of aggressive bone cancer. Current treatment strategies include surgical resection, radiation, and chemotherapy. Doxorubicin has been widely used as a chemotherapeutic drug to treat osteosarcoma. However, drug resistance has become a challenge to its use. In this study, p53-wild type U2OS and p53-null MG-63 osteosarcoma-derived cells were used to investigate the mechanism of doxorubicin-induced cytotoxicity. In cell viability assays, doxorubicin effectively induced apoptosis in U2OS cells via the p53 signaling pathway, evidenced by elevated PUMA and p21 protein levels and activated caspase 3 cleavage. In contrast, p53-null MG-63 cells were resistant to doxorubicin-induced apoptosis, while exogenous expression of p53 increased drug sensitivity in those cells. The role of TGF-β/Smad3 signaling was investigated by using TGF-β reporter luciferase assays. Doxorubicin was able to induce TGF-β signal transduction without increasing TGF-β production in the presence of p53. Knockdown of Smad3 expression by small hairpin RNA (shRNA) showed that Smad3 was required for p53-mediated TGF-β signaling in response to doxorubicin treatment in U2OS and MG-63 cells. Taken together, these data demonstrate that p53 and TGF-β/Smad3 signaling pathways are both essential for doxorubicin-induced cytotoxicity in osteosarcoma cells.
authors.affiliation: Department of Orthopaedics, Third Hospital of Jilin University 126 Xiantai Street, Changchun 130023, China.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Orthopaedics, Third Hospital of Jilin University 126 Xiantai Street, Changchun 130023, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.affiliation: First Hospital of Jilin University 2699 Xinmin Street, Changchun 130021, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hand Surgery, China-Japan Union Hospital, Jilin University Changchun 130024, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.affiliation: First Hospital of Jilin University 2699 Xinmin Street, Changchun 130021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
keywords: Osteosarcoma; P53; TGF-beta signaling pathway; chemotherapy; doxorubicin