2. Academic Validation
  3. α-Hederin induces human colorectal cancer cells apoptosis through disturbing protein homeostasis

α-Hederin induces human colorectal cancer cells apoptosis through disturbing protein homeostasis

  • Chem Biol Interact. 2023 Oct 28:110785. doi: 10.1016/j.cbi.2023.110785.
Qijuan Wang 1,  Hui Feng 2,  Ziwen Li 2,  Qibiao Wu 3,  Liu Li 4,  Dongdong Sun 4,  Jiani Tan 4,  Minmin Fan 4,  Chengtao Yu 4,  Changliang Xu 4,  Yueyang Lai 4,  Weixing Shen 5,  Haibo Cheng 6
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Zhenjiang Hospital of Integrated Traditional Chinese and Western Medicine, Zhenjiang, 212000, Jiangsu, China.
  • 2 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China.
  • 4 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing, 210023, Jiangsu, China.
  • 5 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing, 210023, Jiangsu, China. Electronic address: [email protected].
  • 6 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China; Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing, 210023, Jiangsu, China; Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China. Electronic address: [email protected].
PMID: 39492501 DOI: 10.1016/j.cbi.2023.110785
Abstract

Protein homeostasis and quality control are crucial for normal cellular activities, and a severe imbalance in protein homeostasis can lead to cell death. α-Hederin, a pentacyclic triterpenoid saponin isolated from Fructus Akebia, has a clear role in promoting colorectal Cancer (CRC) cell Apoptosis and has been recently used for CRC therapy. However, whether the pro-apoptotic activity of α-hederin in CRC cells involves disturbing protein homeostasis remains unknown. Here, we aimed to uncover the underlying molecular mechanism of α-hederin-induced Apoptosis in CRC cells. Cell viability and proliferation were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assays, respectively. Apoptosis was detected using flow cytometry and western blotting. Autophagic flux was examined by western blotting and AdPlus-mCherry-GFP-LC3B adenovirus Infection assays, and western blotting and immunofluorescence staining were performed to detect the expression of proteins in related pathways. The results showed that α-hederin significantly inhibited the growth and promoted the Apoptosis of human CRC cells. Furthermore, α-Hederin induced endoplasmic reticulum (ER) stress, but inhibited proteasomal degradation. Also, the autophagic flux was blocked by α-hederin although this drug promoted autophagosome formation, and the lysosomal degradation was inhibited. Expression of p-JNK and p-p38 were increased by α-hederin. So, our findings provide strong evidence that α-hederin disrupts protein homeostasis by blocking ER-associated degradation (ERAD) and autophagic flux, thereby contributing to Apoptosis. PERK-eIF2α-ATF4-CHOP and IRE1-ASK1-JNK/p38 signal pathway may be involved in those regulation. Our results make it a promising alternative or adjunct therapeutic candidate for CRC.

Keywords

Apoptosis; Autophagic flux; Colorectal cancer; Endoplasmic reticulum-associated degradation; protein homeostasis; α-Hederin.

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