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A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor characterized by diffuse growth. DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL. This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines. Cell Counting Kit-8 (CCK-8) and plate colony formation assays were used to evaluate cell proliferation levels. Flow cytometry was employed to analyze apoptosis and the cell cycle, and western blotting was used to quantify the expression of cell cycle regulators. The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells. Moreover, DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways. DCZ0858 also induced cell cycle arrest in the G0/G1 phase, thereby controlling cell proliferation. Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment. Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells, while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells. Moreover, a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib, and combining the two could significantly enhance cancer-suppressive signaling. Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs, findings that were consistent with the in vitro data. In summary, DCZ0858 is a promising drug for the treatment of DLBCL.

SUBMITTER: Lu K

PROVIDER: S-EPMC7118088 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway.

Lu Kang K Li Bo B Zhang Hui H Xu Zhijian Z Song Dongliang D Gao Lu L Sun Haiguo H Li Liping L Wang Yingcong Y Feng Qilin Q Chen Gege G Hu Liangning L Wei Rong R Xie Yongsheng Y Yu Dandan D Wu Xiaosong X Zhu Weiliang W Shi Jumei J

Signal transduction and targeted therapy 20200401 1

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor characterized by diffuse growth. DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL. This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines. Cell Counting Kit-8 (CCK-8) and plate colony formation assays were used to evaluate cell proliferation levels. Flow cytometry was employed to analyze apoptosis and the cell cycle, and western blotting was used to quantify the e ...[more]

PMID: 32296013

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Project description:Diffuse large B‑cell lymphoma (DLBCL) remains difficult to treat clinically due to its highly aggressive characteristics. Insulin‑like growth factor 2 mRNA‑binding protein 2 (IGF2BP2) and 5'‑nucleotidase domain‑containing 2 (NT5DC2) have been suggested as potential regulators in numerous types of cancer. The present study aimed to determine whether downregulation of IGF2BP2 and NT5DC2 suppresses cell proliferation, and induces cell cycle arrest and apoptosis in DLBCL cells by regulating the p53 signaling pathway. The expression levels of IGF2BP2 and NT5DC2 in DLBCL cells were determined by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. Transfection of cells with IGF2BP2 overexpressing plasmids and NT5DC2 interference plasmids was performed, and the efficacy of transfection was confirmed by RT‑qPCR and western blot analysis. The viability, proliferation, cell cycle progression and apoptosis of DLBCL cells were analyzed by Cell Counting Kit‑8 assay, 5‑bromo‑2‑deoxyuridine staining and flow cytometry. RNA pull‑down and immunoprecipitation assays were used to verify the binding of IGF2BP2 and NT5DC2. The expression levels of apoptosis, cell cycle and p53 pathway‑associated proteins were determined by western blotting. The results revealed that NT5DC2 expression was increased in DLBCL cell lines and was the highest in OCI‑Ly7 cells. IGF2BP2 expression was also increased in OCI‑Ly7 cells and IGF2BP2 bound to NT5DC2. Knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells, which was reversed by upregulation of IGF2BP2. In addition, knockdown of NT5DC2 increased the expression of p53 and p21, but suppressed the expression of proliferating cell nuclear antigen, CDK4 and cyclin D1; these effects were reversed by upregulation of IGF2BP2. In conclusion, knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells by regulating the p53 signaling pathway and these effects were reversed by upregulation of IGF2BP2.

Dataset Information

A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway.

Publications

A novel silicone derivative of natural osalmid (DCZ0858) induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway.

Similar Datasets

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