Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the...Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.展开更多
Objective:To explore the toxicity and cellular uptake of the self-synthesized second mitochondria-derived activator of caspase(SMAC)mimetic TP-WY-1345 polypeptide and its radiosensitizing effect on non-small cell lung...Objective:To explore the toxicity and cellular uptake of the self-synthesized second mitochondria-derived activator of caspase(SMAC)mimetic TP-WY-1345 polypeptide and its radiosensitizing effect on non-small cell lung cancer(NSCLC).Methods:A fluorescence microscope was used to observe the uptake efficiency of TP-WY-1345 by human NSCLC cells H1299.Toxicity of the TP-WY-1345 peptide in normal cells was examined in human embryonic lung fibroblasts MRC5.CCK-8 and clone formation experiments were performed to detect the radiosensitizing effect of TP-WY-1345 in the H1299 cells.The AutoDock Vina simulation software was employed to predict the binding efficiency of TP-WY-1345 to the inhibitor of apoptosis proteins(IAPs).Moreover,Western blot and qPCR experiments were carried out to determine the protein and gene expressions,and the flow cytometry(FCM)technique was used to detect the apoptosis level under different conditions.Results:TP-WY-1345 can be self-synthesized,and significant green fluorescence was observed in H12992 h and 6 h after incubation with TP-WY-1345.The cell counting and CCK-8 results showed that 10μmol/L and 20μmol/L TP-WY-1345 did not produce a significant toxic effect on the MRC5 cells(P>0.05).Compared with the single ionizing radiation group,the cell viability and clone formation of H1299 cells were significantly inhibited after treatment with TP-WY-1345 at a concentration of 50μmol/L(P<0.05).The sensitivity enhancement ratio(SER)was calculated to be 1.14.Moreover,the binding efficiency of TP-WY-1345 to cIAP1 protein was predicted to be7.3,and this strong binding force was demonstrated by Western blot.TP-WY-1345 inhibited the protein and mRNA expressions of cIAP1 and further increased the apoptosis level of the H1299 cells at 24 h(P<0.01)and 48 h after radiation(P<0.05).Conclusion:SMAC mimetic TP-WY-1345 can enter the H1299 cells and produce a radiosensitizing effect by increasing the level of radiation-induced apoptosis of the cells.There,TP-WY-1345 is expected to become a new generation of radiosensitizing drugs.展开更多
基金supported by grants JCYJ20220818102611025 and RCYX20210706092040044 from the Science and Technology Foundation of Shenzhengrant 82071193 from the National Natural Science Foundation of China+4 种基金grant 0920220233 from the Guangdong Zhujiang Programsupported by grant JCYJ20240813094605008 from the Shenzhen Natural Science Foundationgrant D2301007 from the Shenzhen Medical Research Fundgrant 2023A1515110237 from the Guangdong Province Basic and Applied Basic Research Foundationgrant 32400577 from the National Natural Science Foundation of China。
文摘Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.
基金This study was supported by the National Natural Science Foundation of China(31971168,32171239).
文摘Objective:To explore the toxicity and cellular uptake of the self-synthesized second mitochondria-derived activator of caspase(SMAC)mimetic TP-WY-1345 polypeptide and its radiosensitizing effect on non-small cell lung cancer(NSCLC).Methods:A fluorescence microscope was used to observe the uptake efficiency of TP-WY-1345 by human NSCLC cells H1299.Toxicity of the TP-WY-1345 peptide in normal cells was examined in human embryonic lung fibroblasts MRC5.CCK-8 and clone formation experiments were performed to detect the radiosensitizing effect of TP-WY-1345 in the H1299 cells.The AutoDock Vina simulation software was employed to predict the binding efficiency of TP-WY-1345 to the inhibitor of apoptosis proteins(IAPs).Moreover,Western blot and qPCR experiments were carried out to determine the protein and gene expressions,and the flow cytometry(FCM)technique was used to detect the apoptosis level under different conditions.Results:TP-WY-1345 can be self-synthesized,and significant green fluorescence was observed in H12992 h and 6 h after incubation with TP-WY-1345.The cell counting and CCK-8 results showed that 10μmol/L and 20μmol/L TP-WY-1345 did not produce a significant toxic effect on the MRC5 cells(P>0.05).Compared with the single ionizing radiation group,the cell viability and clone formation of H1299 cells were significantly inhibited after treatment with TP-WY-1345 at a concentration of 50μmol/L(P<0.05).The sensitivity enhancement ratio(SER)was calculated to be 1.14.Moreover,the binding efficiency of TP-WY-1345 to cIAP1 protein was predicted to be7.3,and this strong binding force was demonstrated by Western blot.TP-WY-1345 inhibited the protein and mRNA expressions of cIAP1 and further increased the apoptosis level of the H1299 cells at 24 h(P<0.01)and 48 h after radiation(P<0.05).Conclusion:SMAC mimetic TP-WY-1345 can enter the H1299 cells and produce a radiosensitizing effect by increasing the level of radiation-induced apoptosis of the cells.There,TP-WY-1345 is expected to become a new generation of radiosensitizing drugs.
