Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophospha...Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy.However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4(DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot(WB) and Flow cytometry(FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II(LC_(3)II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the m TOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.展开更多
Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 pro...Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia(AMoL)cells.However,the mechanism has not been elucidated.Here,by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34(Molm13-IL-34 and THP1-IL-34),upregulation of the DNA damageinducible transcript 4(DDIT4)was detected in both series.Knockdown of DDIT4 effectively inhibited the proliferation,promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells.Our results suggest that DDIT4 mediates the proliferationpromotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.展开更多
Chronic myeloid leukemia(CML)is a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitors(TKIs),due to BCR::ABL1 mutations and residual leukemia stem cells(LSCs),rema...Chronic myeloid leukemia(CML)is a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitors(TKIs),due to BCR::ABL1 mutations and residual leukemia stem cells(LSCs),remains a major challenge in CML treatment.Here,we revealed the requirement of the vitamin D receptor(VDR)in the progression of CML.VDR was upregulated by BCR::ABL1 and highly expressed in CML cells.Interestingly,VDR knockdown inhibited the proliferation of CML cells driven by both BCR::ABL1 and TKI-resistant BCR::ABL1 mutations.Mechanistically,VDR transcriptionally regulated DDIT4 expression;reduced DDIT4 levels upon VDR knockdown triggered DNA damage and senescence via p53 signaling activation in CML cells.Furthermore,VDR deficiency not only suppressed tumor burden and progression in primary CML mice but also reduced the self-renewal capacity of CML-LSCs.Together,our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate LSCs in CML.展开更多
基金supported by the National Key Research and Development Program of China (No. 2018YFC1603704)the Tianjin Natural Science Foundation (No. 20JCQNJC00860)。
文摘Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy.However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4(DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot(WB) and Flow cytometry(FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II(LC_(3)II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the m TOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.
基金This work was supported by grants 81770183 and 81970155 from the National Natural Science Foundation of China(NSFC)programs 2016-I2M-2-006 and 2017-I2M-1-015 from the CAMS Innovation Fund for Medical Sciences(CIFMS)+1 种基金State Key Laboratory of Experimental Hematology Research Grant(Z20-06)G.Z.is a recipient of the New Century Excellent Talents in University(NCET-08–0329).
文摘Interleukin 34(IL-34)is a cytokine that shares the receptor with colony-stimulating factor 1(CSF-1).IL-34 is involved in a broad range of pathologic processes including cancer.We previously demonstrated that IL-34 promoted the proliferation and colony formation of human acute monocytic leukemia(AMoL)cells.However,the mechanism has not been elucidated.Here,by analyzing the gene profiles of Molm13 and THP1 cells overexpressing IL-34(Molm13-IL-34 and THP1-IL-34),upregulation of the DNA damageinducible transcript 4(DDIT4)was detected in both series.Knockdown of DDIT4 effectively inhibited the proliferation,promoted apoptosis and colony formation in Molm13-IL-34 and THP1-IL-34 cells.Our results suggest that DDIT4 mediates the proliferationpromotive effect of IL-34 whereas does not mediate the promotive effect of IL-34 on colony formation in AMoL cells.
基金supported by grants from the National Natural Science Foundation of China(81874294)the Taishan Scholars Program(TSQN201812015)+3 种基金the program for Multidisciplinary Research and Innovation Team of Young Scholars of Shandong University(2020QNQT007)the key Program of the Natural Science Foundation of Shandong Province(ZR2022LSW027)This work was also supported by the program for Innovative Research Team at the University of Ministry of Education of China(IRT_17R68)the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology(WZCX2021-03).
文摘Chronic myeloid leukemia(CML)is a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitors(TKIs),due to BCR::ABL1 mutations and residual leukemia stem cells(LSCs),remains a major challenge in CML treatment.Here,we revealed the requirement of the vitamin D receptor(VDR)in the progression of CML.VDR was upregulated by BCR::ABL1 and highly expressed in CML cells.Interestingly,VDR knockdown inhibited the proliferation of CML cells driven by both BCR::ABL1 and TKI-resistant BCR::ABL1 mutations.Mechanistically,VDR transcriptionally regulated DDIT4 expression;reduced DDIT4 levels upon VDR knockdown triggered DNA damage and senescence via p53 signaling activation in CML cells.Furthermore,VDR deficiency not only suppressed tumor burden and progression in primary CML mice but also reduced the self-renewal capacity of CML-LSCs.Together,our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate LSCs in CML.
