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Published on: March 18, 2014
Apoptotic effect and cell arrest of deoxyshikonin in human osteosarcoma cells through the p38 pathway
Ming-Chang Hsieh1,2, Yi-Hsien Hsieh3,4, Chia-Hsuan Chou3,4
1School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
Abstract:
Osteosarcoma is the most common primary bone cancer that affects adolescents with early metastatic potential and drastically reduces their long-term survival rate if pulmonary metastases are detected at diagnosis. The natural naphthoquinol compound deoxyshikonin exhibits anticancer properties, so we hypothesized that it has an apoptotic effect on osteosarcoma U2OS and HOS cells and studied its mechanisms. After deoxyshikonin treatment, dose-dependent decreases in cell viability, induction of cell apoptosis and arrest in the sub-G1 phase of U2OS and HOS cells were observed. The increases in cleaved caspase 3 expression and the decreases in X-chromosome-linked IAP (XIAP) and cellular inhibitors of apoptosis 1 (cIAP-1) expressions after deoxyshikonin treatment in the human apoptosis array were identified in HOS cells, and dose-dependent expression changes of IAPs and cleaved caspase 3, 8 and 9 were verified by Western blotting in U2OS and HOS cells. Phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2 and p38 expressions in U2OS and HOS cells was also increased by deoxyshikonin in a dose-dependent manner. Subsequently, cotreatment with inhibitors of ERK (U0126), JNK (JNK-IN-8) and p38 (SB203580) was performed to show that p38 signalling is responsible for deoxyshikonin-induced apoptosis in U2OS and HOS cells, but not via the ERK and JNK pathways. These discoveries demonstrate that deoxyshikonin may be a possible chemotherapeutic candidate to induce cell arrest and apoptosis by activating extrinsic and intrinsic pathways through p38 for human osteosarcoma.
Insights
Deoxyshikonin, a natural compound, effectively induces apoptosis and cell cycle arrest in osteosarcoma cells. Its mechanism involves activating the p38 signaling pathway, suggesting potential as a novel cancer therapeutic.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Osteosarcoma is a primary bone cancer common in adolescents, characterized by early metastasis and poor survival rates.
- The natural compound deoxyshikonin possesses known anticancer properties.
- Investigating deoxyshikonin's effects on osteosarcoma cell lines is crucial for potential therapeutic development.
Purpose of the Study:
- To investigate the apoptotic effects of deoxyshikonin on human osteosarcoma U2OS and HOS cells.
- To elucidate the underlying molecular mechanisms of deoxyshikonin-induced apoptosis.
- To evaluate the role of specific signaling pathways, including p38, ERK, and JNK, in deoxyshikonin's action.
Main Methods:
- Treatment of U2OS and HOS cells with varying concentrations of deoxyshikonin.
- Assessment of cell viability, apoptosis, and cell cycle phase distribution (sub-G1).
- Analysis of apoptosis-related protein expression (caspase 3, XIAP, cIAP-1) using human apoptosis array and Western blotting.
- Evaluation of mitogen-activated protein kinase (MAPK) pathway activation (ERK, JNK, p38) via Western blotting.
- Pharmacological inhibition of ERK, JNK, and p38 pathways to determine their role in deoxyshikonin's effects.
Main Results:
- Deoxyshikonin treatment resulted in dose-dependent decreases in cell viability and induced apoptosis and sub-G1 cell cycle arrest in osteosarcoma cells.
- Expression of cleaved caspase 3 increased, while XIAP and cIAP-1 levels decreased following deoxyshikonin treatment.
- Deoxyshikonin treatment led to dose-dependent phosphorylation of ERK, JNK, and p38 signaling proteins.
- Inhibition of the p38 pathway, but not ERK or JNK, abrogated deoxyshikonin-induced apoptosis, indicating p38's critical role.
Conclusions:
- Deoxyshikonin effectively induces cell cycle arrest and apoptosis in human osteosarcoma cells.
- The mechanism involves the activation of both extrinsic and intrinsic apoptotic pathways, primarily mediated by the p38 signaling pathway.
- Deoxyshikonin shows promise as a potential chemotherapeutic agent for osteosarcoma treatment.
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