PP9, a steroidal saponin, induces G2/M arrest and apoptosis in human colorectal cancer cells by inhibiting the PI3K/Akt/GSK3β pathway.

Abstract

Colorectal cancer (CRC) represents one of the commonest malignancies around the world. PP9, a natural steroidal saponin, was firstly isolated from the rhizomes of Paris polyphylla var. latifolia. However, the therapeutic effects of PP9 on CRC and the underlying molecular mechanism remain undefined. Here, we demonstrated that treatment with PP9 time- and dose-dependently inhibited HT-29 and HCT116 cells without significantly inhibiting normal NCM460 cells. Furthermore, our results indicated that PP9 effectively induced G2/M phase arrest by upregulating p21 and suppressing cdc25C, Cyclin B1 and cdc2. Meanwhile, PP9 upregulated cleaved Caspase 3, cleaved Caspase 9 and cleaved PARP and Bax, while downregulating Bcl-2 to stimulate cell apoptosis. Mechanistically, PP9-suppressed PI3K/Akt/GSK3β signaling, while the PI3K inhibitor LY294002 augmented PP9-mediated apoptosis, G2/M arrest and effects on PI3K/Akt/GSK3β related proteins. Finally, we showed that PP9 (10 mg/kg) significantly reduced tumor growth in nude mouse CRC xenografts, more potently than 5-Fu (20 mg/kg). Jointly, these data firstly demonstrated that PP9 promotes G2/M arrest and apoptotic death in CRC cells through PI3K/Akt/GSK3β signaling suppression, suggesting that PP9 could be considered a new and promising candidate for CRC therapy.

• Authors: Minna Yao, Ruili Li, Zhifu Yang, Yi Ding, Wei Zhang, Weiwei Li, Meiyou Liu, Chao Zhao, Yanhua Wang, Haifeng Tang, Jingwen Wang, Aidong Wen
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 331 Pg. 109246 (Nov 01 2020) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 32877639 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Chromones
• Morpholines
• Proto-Oncogene Proteins c-bcl-2
• Saponins
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Chromones (pharmacology)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Liliales (chemistry, metabolism)
• M Phase Cell Cycle Checkpoints (drug effects)
• Male
• Mice
• Mice, Nude
• Morpholines (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Saponins (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Transplantation, Heterologous