| Residential College | false |
| Status | 已發表Published |
| Pulchinenoside E4 sensitizes chemotherapy against breast cancer through blocking autophagic flux | |
ZHAO Yuxin; HE CHENGWEI 
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| 2022-10 | |
| Publisher | Internal communicationa |
| Conference Name | 8th Macau Symposium on Biomedical Science 2022 (MSBS2022) |
| Conference Place | Macau |
| Conference Date | 2022-10-14--2022-10-15 |
| Country | China |
| Abstract | Autophagy is an intracellular protective process involving degradation of misfolded proteins, damaged organelles and nucleic acids in lysosomes to maintain homeostasis under stressful conditions. Present evidence shows that autophagy inhibitors can improve the pathologic tumor and serum biomarkers responding to chemotherapeutic drugs. Pulchinenoside E4 (PSE4) is a triterpenoid isolated from Pulsatilla chinensis (Bunge) Regel, a traditional Chinese medicinal herb used for the treatment of inflammation and infection. It was reported that some triterpenoids exhibited anti-cancer and autophagy inhibitory effect. The present study focuses on the autophagy inhibition caused by PSE4 and its underlying mechanisms, as well as its synergistic anti-breast cancer activity. Results revealed that PSE4 induced autophagosome formation but interrupted the autophagosome-lysosome fusion process in breast cancer cells (MCF-7 and MDA-MB-231 cell lines). As a result, autophagic flux was inhibited. Alexa Fluor 594-conjugated CTxB staining showed that lysosomal lipid rafts were disrupted by PSE4. However, when adding cholesterol, which is protective to lipid rafts, the decreased fluorescence of CTxB caused by PSE4 was partially recovered, further demonstrating the destructive effect of PSE4 on lipid rafts. The variation of protein LC3I, LC3II and p62 suggested this lipid raft disruption was directly related to the autophagic flux inhibition. Lysosomal acidification and activation of cathepsins in lysosomes were also interfered. PSE4 significantly elevated lysosomal pH, which is comparable to chloroquine, a known lysosomal alkalizing agent that strongly inhibited autophagy. Inhibition of cathepsin activity in lysosomes has been proved to be associated with increased lysosomal pH and lipid rafts destruction on lysosome membrane. Furthermore, inhibition of autophagy by PSE4 (1.5, 3, 6 μM) could enhance the anti-breast cancer activity of 5-fluorouracil in vitro and in vivo. Taken together, PSE4 inhibits autophagic flux and thereby sensitizes chemotherapy against breast cancer through disrupting lysosomal structure and function. |
| Keyword | Pulchinenoside E4 Breast Cancer Chemotherapy Autophagy Lipid Rafts |
| Document Type | Conference proceedings |
| Collection | Institute of Chinese Medical Sciences |
| Corresponding Author | HE CHENGWEI |
| Affiliation | University of Macau |
| First Author Affilication | University of Macau |
| Recommended Citation GB/T 7714 | ZHAO Yuxin,HE CHENGWEI. Pulchinenoside E4 sensitizes chemotherapy against breast cancer through blocking autophagic flux[C]:Internal communicationa, 2022. |
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| 2022 8th Macau Sympo（29175KB） | 会议录 | 开放获取 | CC BY-NC-SA | View Download | ||
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