DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway.

Abstract

BACKGROUND:

Emerging hallmark of cancer is reprogrammed cellular metabolism, increased glycolytic metabolism is physiological characteristic of human malignant neoplasms. Saponin monomer 13 of the dwarf lilyturf tuber (DT-13) is the main steroidal saponin from Liriopes Radix, which has been reported to exert anti-inflammation and anti-tumor activities but low toxicity to normal tissue. However, the effect of DT-13 on metabolism process is still unclear.

PURPOSE:

This study aims to characterize the role of DT-13 in glucose metabolism in colorectal cancer cells, and investigate whether the metabolism process is involved in the anti-cancer response of DT-13.

METHODS:

Colony formation assay was employed to determine anti-proliferative effect induced by DT-13 at 2.5, 5, 10 μM. Apoptosis and cell cycle arrest were detected by Annexin V/PI staining and PI staining, respectively. Genetic inhibition of glycolytic metabolism was carried out by knockdown of GLUT1. Orthotopic implantation mouse model of colorectal cancer was used to assess in vivo antitumor effect of DT-13 (0.625, 1.25, 2.5 mg/kg). The chemoprevention effect of DT-13 (10mg/kg) was evaluated by using C57BL/6J APCmin mice model. Glycolytic-related key enzymes and AMPK pathway were detected by using quantitative real-time PCR, western blotting, and immunohistochemical staining.

RESULTS:

Our results showed that cell proliferation was significantly inhibited by DT-13 in a dose-dependent manner. DT-13 inhibited glucose uptake, ATP generation, and reduced lactate production. Furthermore, DT-13 remarkably inhibited GLUT1 expression in both mRNA and protein levels. Knocking down of GLUT1 led to reduced inhibition of glucose uptake after DT-13 treatment. Moreover, deletion of GLUT1 decreased inhibitory ratio of DT-13 on cancer growth. Orthotopic implantation mouse model of colorectal cancer further confirmed that DT-13 inhibited colorectal cancer growth via blocking GLUT1 in vivo. In addition, C57BL/6J APCmin mice model revealed that DT-13 dramatically reduced the total number of spontaneous adenomas in intestinal, which further confirmed the anti-tumor activity of DT-13 in colorectal cancer. Furthermore, the mechanistically investigation showed DT-13 activated AMPK and inhibited m-TOR to block cancer growth in vitro.

CONCLUSION:

DT-13 is a potent anticancer agent for colorectal cancer.

• Authors: Xiaohui Wei, Tingting Mao, Sijing Li, Jinyong He, Xiaoying Hou, Hongyang Li, Meixiao Zhan, Xiangyu Yang, Ruiming Li, Jing Xiao, Shengtao Yuan, Li Sun
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 54 Pg. 120-131 (Feb 15 2019) ISSN: 1618-095X [Electronic] Germany
• PMID: 30668361 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier GmbH.

Chemical References

• Antineoplastic Agents, Phytogenic
• Glucose Transporter Type 1
• SLC2A1 protein, human
• Saponins
• ruscogenin-1-O-(glucopyranosyl-(1-2))(xylopyranosyl-(1-3))fucopyranoside
• MTOR protein, human
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Female
• Glucose Transporter Type 1 (antagonists & inhibitors, genetics, metabolism)
• Glycolysis
• Humans
• Liriope Plant (chemistry)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Saponins (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays