穿心莲内酯通过 ROS/JNK 通路诱导人骨肉瘤细胞凋亡。
- 作者列表："Wang S","Li H","Chen S","Wang Z","Yao Y","Chen T","Ye Z","Lin P
:Osteosarcoma is the most common primary malignant tumor of the bone and the long‑term survival of patients with this disease has remained unsatisfactory over the past several decades. Andrographolide, a traditional drug used in Chinese medicine, has been found to exert a significant antitumor effect against several types of cancer. However, relatively little is known about the effect of andrographolide on osteosarcoma and the underlying mechanisms. In the present study, it was shown that andrographolide inhibited osteosarcoma cell proliferation by arresting the cell cycle at the G2/M phase and increasing caspase‑mediated apoptosis. Furthermore, treatment with andrographolide induced JNK activation and increased production of reactive oxygen species (ROS). The andrographolide‑triggered apoptosis in osteosarcoma cells was partly abrogated by a JNK inhibitor and completely reversed by a ROS scavenger. Additionally, JNK activation and cell cycle arrest at the G2/M phase were prevented by administration of an ROS scavenger. In vivo, it was also found that andrographolide inhibited tumor growth by increasing the levels of ROS and activating JNK; thus inducing cytotoxicity in primary osteosarcoma cells. Together, the results of the present study suggest that andrographolide caused G2/M arrest and induced cell apoptosis via regulation of the ROS/JNK signaling pathway in osteosarcoma cells. Thus, andrographolide may serve as a promising antitumor therapeutic agent against osteosarcoma.
: 骨肉瘤是最常见的骨原发性恶性肿瘤，在过去几十年中，这种疾病患者的长期生存率一直不令人满意。穿心莲内酯，一种传统的中药，已被发现对几种类型的癌症发挥显著的抗肿瘤作用。然而，穿心莲内酯对骨肉瘤的作用及其机制相对知之甚少。本研究表明，穿心莲内酯通过将细胞周期阻滞在 G2/M 期和增加 caspase 介导的凋亡来抑制骨肉瘤细胞增殖。此外，穿心莲内酯治疗诱导 JNK 活化和活性氧 (ROS) 产生增加。穿心莲内酯触发的骨肉瘤细胞凋亡部分被 JNK 抑制剂清除，并被 ROS 清除剂完全逆转。此外，通过给予 ROS 清除剂可阻止 JNK 激活和细胞周期阻滞在 G2/M 期。在体内，还发现穿心莲内酯通过提高 ROS 水平和激活 JNK 抑制肿瘤生长; 从而诱导原代骨肉瘤细胞的细胞毒性。总之，本研究结果表明，穿心莲内酯通过调控 ROS/JNK 信号通路引起骨肉瘤细胞 G2/M 期阻滞并诱导细胞凋亡。因此，穿心莲内酯可能作为一种有前途的抗肿瘤治疗骨肉瘤的药物。
METHODS:BACKGROUND:Osteosarcoma is the most common primary bone malignancy in children and adolescents. In order to find factors related to its recurrence, and thus improve recovery prospects, a powerful clinical signature is needed. Long noncoding RNAs (lncRNAs) are essential in osteosarcoma processes and development, and here we report significant lncRNAs to aid in earlier diagnosis of osteosarcoma. METHODS:A univariate Cox proportional hazards regression analysis and a multivariate Cox regression analysis were used to analyze osteosarcoma patients' lncRNA expression data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET), a public database. RESULTS:A lncRNA signature consisting of three lncRNAs (RP1-261G23.7, RP11-69E11.4 and SATB2-AS1) was selected. The signature was used to sort patients into high-risk and low-risk groups with meaningful recurrence rates (median recurrence time 16.80 vs. >128.22 months, log-rank test, P143.80 months, log-rank test, P=0.006). A multivariate Cox regression analysis showed that the significant lncRNA was an independent prognostic factor for osteosarcoma patients. Functional analysis suggests that these lncRNAs were related to the PI3K-Akt signaling pathway, the Wnt signaling pathway, and the G-protein coupled receptor signaling pathway, all of which have various, important roles in osteosarcoma development. The significant 3-lncRNA set could be a novel prediction biomarker that could aid in treatment and also predict the likelihood of recurrence of osteosarcoma in patients.
METHODS::Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.
METHODS:PURPOSE:The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities. METHODS:We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients. RESULTS:A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively (P = .007), and 5-year event-free survival (EFS) was 51% versus 58% (P = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% (P < .001), and 5-year EFS was 36% versus 56% (P < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS (P = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS (P = .263; HR, 1.312). CONCLUSION:In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.