Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism

Jae Hyun Kim, Kyoung Jin Lee, Yoojeong Seo, Ji Hee Kwon, Jae Pil Yoon, Jo Yeon Kang, Hyun Jung Lee, Soo Jung Park, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim, Tae Kim

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin. A combination of metformin and glutaminase C inhibitor (compound 968) suppressed CSCs in SW620 cells and enhanced that effect in HT29 cells. SW620 cells showed higher expression of glutaminase 1 and glutamine transporter (ASCT2) than HT29 cells, especially ASCT2 in CSCs. Knockdown of glutaminase 1, ASCT2, and c-Myc induced significant CSC-suppression and enhanced CSC-suppressing effect of metformin and compound 968. In xenografts and human cancer organoids, combined treatment with metformin and compound 968 showed the same results as those shown in vitro. In conclusion, the effect of metformin on CSCs varies depending on the AMPK-mTOR and glutamine metabolism. The inhibition of glutamine pathway could enhance the CSC-suppressing effect of metformin, overcoming metformin resistance.

Original languageEnglish
Article number409
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Neoplastic Stem Cells
Metformin
Glutamine
Colorectal Neoplasms
HT29 Cells
Glutaminase
Organoids
AMP-Activated Protein Kinases
Heterografts
Oxygen Consumption
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

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Kim, J. H., Lee, K. J., Seo, Y., Kwon, J. H., Yoon, J. P., Kang, J. Y., ... Kim, T. (2018). Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism. Scientific reports, 8(1), [409]. https://doi.org/10.1038/s41598-017-18762-4
Kim, Jae Hyun ; Lee, Kyoung Jin ; Seo, Yoojeong ; Kwon, Ji Hee ; Yoon, Jae Pil ; Kang, Jo Yeon ; Lee, Hyun Jung ; Park, Soo Jung ; Hong, Sung Pil ; Cheon, Jae Hee ; Kim, Won Ho ; Kim, Tae. / Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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abstract = "Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin. A combination of metformin and glutaminase C inhibitor (compound 968) suppressed CSCs in SW620 cells and enhanced that effect in HT29 cells. SW620 cells showed higher expression of glutaminase 1 and glutamine transporter (ASCT2) than HT29 cells, especially ASCT2 in CSCs. Knockdown of glutaminase 1, ASCT2, and c-Myc induced significant CSC-suppression and enhanced CSC-suppressing effect of metformin and compound 968. In xenografts and human cancer organoids, combined treatment with metformin and compound 968 showed the same results as those shown in vitro. In conclusion, the effect of metformin on CSCs varies depending on the AMPK-mTOR and glutamine metabolism. The inhibition of glutamine pathway could enhance the CSC-suppressing effect of metformin, overcoming metformin resistance.",
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Kim, JH, Lee, KJ, Seo, Y, Kwon, JH, Yoon, JP, Kang, JY, Lee, HJ, Park, SJ, Hong, SP, Cheon, JH, Kim, WH & Kim, T 2018, 'Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism', Scientific reports, vol. 8, no. 1, 409. https://doi.org/10.1038/s41598-017-18762-4

Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism. / Kim, Jae Hyun; Lee, Kyoung Jin; Seo, Yoojeong; Kwon, Ji Hee; Yoon, Jae Pil; Kang, Jo Yeon; Lee, Hyun Jung; Park, Soo Jung; Hong, Sung Pil; Cheon, Jae Hee; Kim, Won Ho; Kim, Tae.

In: Scientific reports, Vol. 8, No. 1, 409, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism

AU - Kim, Jae Hyun

AU - Lee, Kyoung Jin

AU - Seo, Yoojeong

AU - Kwon, Ji Hee

AU - Yoon, Jae Pil

AU - Kang, Jo Yeon

AU - Lee, Hyun Jung

AU - Park, Soo Jung

AU - Hong, Sung Pil

AU - Cheon, Jae Hee

AU - Kim, Won Ho

AU - Kim, Tae

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin. A combination of metformin and glutaminase C inhibitor (compound 968) suppressed CSCs in SW620 cells and enhanced that effect in HT29 cells. SW620 cells showed higher expression of glutaminase 1 and glutamine transporter (ASCT2) than HT29 cells, especially ASCT2 in CSCs. Knockdown of glutaminase 1, ASCT2, and c-Myc induced significant CSC-suppression and enhanced CSC-suppressing effect of metformin and compound 968. In xenografts and human cancer organoids, combined treatment with metformin and compound 968 showed the same results as those shown in vitro. In conclusion, the effect of metformin on CSCs varies depending on the AMPK-mTOR and glutamine metabolism. The inhibition of glutamine pathway could enhance the CSC-suppressing effect of metformin, overcoming metformin resistance.

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