Metformin Suppresses Cancer Stem Cells through AMPK Activation and Inhibition of Protein Prenylation of the Mevalonate Pathway in Colorectal Cancer

被引:42
|
作者
Seo, Yoojeong [1 ,2 ]
Kim, Janghyun [1 ]
Park, Soo Jung [1 ,3 ]
Park, Jae Jun [1 ,3 ,4 ]
Cheon, Jae Hee [1 ,3 ]
Kim, Won Ho [1 ,3 ]
Kim, Tae Il [1 ,2 ,3 ,4 ]
机构
[1] Yonsei Univ, Coll Med, Inst Gastroenterol, Seoul 03722, South Korea
[2] Yonsei Univ, Coll Med, Brain Korea PLUS Project Med Sci 21, Seoul 03722, South Korea
[3] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 03722, South Korea
[4] Yonsei Univ, Coll Med, Canc Prevent Ctr, Seoul 03722, South Korea
基金
新加坡国家研究基金会;
关键词
cancer stem cells; metformin; mevalonate pathway; protein prenylation; colorectal cancer; CHEMOTHERAPY; MECHANISMS; KINASE;
D O I
10.3390/cancers12092554
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary Tumor suppressing effect of metformin has been reported, and one of mechanism of this effect is suppression of cancer stem cells (CSCs). However, detailed mechanism of metformin-induced CSC-inhibitory effect has not been known. We demonstrated that the CSC-suppressive effect of metformin was associated with AMPK activation/mTOR inhibition and repression of protein prenylation through suppression of mevalonate pathway in colorectal cancer. Further studies would be needed to investigate cross-reactions with other mechanisms of the antitumor effect of metformin, and clinical impact of metformin should be considered as chemopreventive or adjunctive treatment for colorectal tumor. Metformin is a well-known AMPK (AMP-activated protein kinase) activator that suppresses cancer stem cells (CSCs) in some cancers. However, the mechanisms of the CSC-suppressing effects of metformin are not yet well understood. In this study, we investigated the CSC-suppressive effect of metformin via the mevalonate (MVA) pathway in colorectal cancer (CRC). Two colorectal cancer cell lines, HT29 and DLD-1 cells, were treated with metformin, mevalonate, or a combination of the two. We measured CSC populations by flow cytometric analysis (CD44+/CD133+) and by tumor spheroid growth. The expression of p-AMPK, mTORC1 (pS6), and key enzymes (HMGCR, FDPS, GGPS1, and SQLE) of the MVA pathway was also analyzed. We investigated the effects of metformin and/or mevalonate in xenograft mice using HT29 cells; immunohistochemical staining for CSC markers and key enzymes of the MVA pathway in tumor xenografts was performed. In both HT29 and DLD-1 cells, the CSC population was significantly decreased following treatment with metformin, AMPK activator (AICAR), HMG-CoA reductase inhibitor (simvastatin), or mTOR inhibitor (rapamycin), and was increased by mevalonate. The CSC-suppressing effect of these drugs was attenuated by mevalonate. The results of tumor spheroid growth matched those of the CSC population experiments. Metformin treatment increased p-AMPK and decreased mTOR (pS6) expression; these effects were reversed by addition of mevalonate. The expression of key MVA pathway enzymes was significantly increased in tumor spheroid culture, and by addition of mevalonate, and decreased upon treatment with metformin, AICAR, or rapamycin. In xenograft experiments, tumor growth and CSC populations were significantly reduced by metformin, and this inhibitory effect of metformin was abrogated by combined treatment with mevalonate. Furthermore, in the MVA pathway, CSC populations were reduced by inhibition of protein prenylation with a farnesyl transferase inhibitor (FTI-277) or a geranylgeranyl transferase inhibitor (GGTI-298), but not by inhibition of cholesterol synthesis with a squalene synthase inhibitor (YM-53601). In conclusion, the CSC-suppressive effect of metformin was associated with AMPK activation and repression of protein prenylation through MVA pathway suppression in colorectal cancer.
引用
收藏
页码:1 / 13
页数:15
相关论文
共 50 条
  • [31] Inhibition of Stearoyl-CoA Desaturase induces cell death and activation of AMPK pathway in cancer cells
    Minville, M.
    Pierre, A. S.
    Gresti, J.
    Fevre, C.
    Bellenger, J.
    Bellenger, S.
    Pichon, L.
    Narce, M.
    Rialland, M.
    EJC SUPPLEMENTS, 2010, 8 (05): : 114 - 114
  • [32] β-Elemene induces apoptosis and autophagy in colorectal cancer cells through regulating the ROS/AMPK/mTOR pathway
    Wang Guo-Yu
    Zhang Lei
    Geng Ya-Di
    Wang Bin
    Feng Xiao-Jun
    Chen Zhao-Lin
    Wei Wei
    Jiang Ling
    CHINESE JOURNAL OF NATURAL MEDICINES, 2022, 20 (01) : 9 - 21
  • [33] β-Elemene induces apoptosis and autophagy in colorectal cancer cells through regulating the ROS/AMPK/mTOR pathway
    WANG GuoYu
    ZHANG Lei
    GENG YaDi
    WANG Bin
    FENG XiaoJun
    CHEN ZhaoLin
    WEI Wei
    JIANG Ling
    Chinese Journal of Natural Medicines, 2022, 20 (01) : 9 - 21
  • [34] Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer
    Honjo, Soichiro
    Ajani, Jaffer A.
    Scott, Ailing W.
    Chen, Qiongrong
    Skinner, Heath D.
    Stroehlein, John
    Johnson, Randy L.
    Song, Shumei
    INTERNATIONAL JOURNAL OF ONCOLOGY, 2014, 45 (02) : 567 - 574
  • [35] WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer
    Eun Ji Ro
    Yong-Hee Cho
    Woo-Jeong Jeong
    Jong-Chan Park
    Do Sik Min
    Kang-Yell Choi
    Cell Communication and Signaling, 17
  • [36] An AMPK agonist suppresses the progress of colorectal cancer by regulating the polarization of TAM to M1 through inhibition of HIF-1α and mTOR signal pathway
    Cao, Yuanyuan
    Wo, Mingyi
    Xu, Chan
    Fei, Xianming
    Jin, Juan
    Shan, Zhiming
    JOURNAL OF CANCER RESEARCH AND THERAPEUTICS, 2023, 19 (06) : 1560 - 1567
  • [37] WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer
    Ro, Eun Ji
    Cho, Yong-Hee
    Jeong, Woo-Jeong
    Park, Jong-Chan
    Min, Do Sik
    Choi, Kang-Yell
    CELL COMMUNICATION AND SIGNALING, 2019, 17 (1)
  • [38] Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway
    Sugiyama, Michiko
    Takahashi, Hirokazu
    Hosono, Kunihiro
    Endo, Hiroki
    Kato, Shingo
    Yoneda, Kyoko
    Nozaki, Yuichi
    Fujita, Koji
    Yoneda, Masato
    Wada, Koichiro
    Nakagama, Hitoshi
    Nakajima, Atsushi
    INTERNATIONAL JOURNAL OF ONCOLOGY, 2009, 34 (02) : 339 - 344
  • [39] A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer
    Choi, Jung Kyu
    Kwak, Ihn-Sil
    Yoon, Sae-Bom
    Cho, Heeyeong
    Moon, Byoung-San
    BIOMEDICINES, 2022, 10 (04)
  • [40] Inhibition of the SHH pathway in colon cancer stem cells
    Penny, C. B.
    Omar, A.
    Ruff, P.
    MOLECULAR BIOLOGY OF THE CELL, 2015, 26