The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an a...The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the m TOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2(labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. EveRh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased cMYC mediated the accumulation of tribbles homolog 3(TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.展开更多
Background:High proliferative rate of cancer cells requires autophagy to maintain nutrient supply and intracellular homeostasis.As a result,impairing autophagic flux could be a novel strategy of cancer therapy.Aims an...Background:High proliferative rate of cancer cells requires autophagy to maintain nutrient supply and intracellular homeostasis.As a result,impairing autophagic flux could be a novel strategy of cancer therapy.Aims and Objectives:In this study,the mechanism of a xanthone derivative isolated from Garcinia mangostana,garcinone E(GE),was investigated.Materials and Methods:Fluorescence assay was used to observe the accumulation and location of autophagosome and lysosome.Flow cytometry with Lyso-tracker red,MDC,and AO staining were applied to evaluate the lysosome accumulation and cellular acidity.Western blot and RT-qPCR were performed to evaluate the protein and mRNA levels,respectively.Results:GE could cause enhancement of LC3 II and p62 and the accumulation of autophagosome and lysosome.Meanwhile,it limited the protein level of Rab7,increased lysosomal pH,and inhibited the maturation of lysosomal hydrolases such as Cathepsin L,therefore blockaded the fusion of autophagosome and lysosome.Moreover,GE acted as a TFEB modulator by downregulating its protein level,which might contribute to autophagy dysfunction in ovarian cancer cells.Conclusions:GE interfered autophagosome–lysosome fusion in cancer cells,which demonstrated its application as an autophagy regulator and a potential therapeutic agent.展开更多
基金supported by the National Natural Science Foundation of China(No.81973516)partially supported by the Science and Technology Development Fund,Macao S.A.R,China(Nos.024/2016/A1 and 0129/2019/A3)University of Macao(No.CPG2021-00022-ICMS)。
文摘The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the m TOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2(labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. EveRh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased cMYC mediated the accumulation of tribbles homolog 3(TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.
基金supported by the Science and Technology Development Fund,Macao SAR(File no.176/2017/A3)
文摘Background:High proliferative rate of cancer cells requires autophagy to maintain nutrient supply and intracellular homeostasis.As a result,impairing autophagic flux could be a novel strategy of cancer therapy.Aims and Objectives:In this study,the mechanism of a xanthone derivative isolated from Garcinia mangostana,garcinone E(GE),was investigated.Materials and Methods:Fluorescence assay was used to observe the accumulation and location of autophagosome and lysosome.Flow cytometry with Lyso-tracker red,MDC,and AO staining were applied to evaluate the lysosome accumulation and cellular acidity.Western blot and RT-qPCR were performed to evaluate the protein and mRNA levels,respectively.Results:GE could cause enhancement of LC3 II and p62 and the accumulation of autophagosome and lysosome.Meanwhile,it limited the protein level of Rab7,increased lysosomal pH,and inhibited the maturation of lysosomal hydrolases such as Cathepsin L,therefore blockaded the fusion of autophagosome and lysosome.Moreover,GE acted as a TFEB modulator by downregulating its protein level,which might contribute to autophagy dysfunction in ovarian cancer cells.Conclusions:GE interfered autophagosome–lysosome fusion in cancer cells,which demonstrated its application as an autophagy regulator and a potential therapeutic agent.
