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Open Access 01-12-2021 | Metformin | Research

Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin

Authors: Se-Kyeong Jang, Sung-Eun Hong, Da-Hee Lee, Ji-Young Kim, Ji Yea Kim, Sang-Kyu Ye, Jungil Hong, In-Chul Park, Hyeon-Ok Jin

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood.

Methods

To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed.

Results

Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib.

Conclusions

ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.

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Title: Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin
Authors: Se-Kyeong Jang
Sung-Eun Hong
Da-Hee Lee
Ji-Young Kim
Ji Yea Kim
Sang-Kyu Ye
Jungil Hong
In-Chul Park
Hyeon-Ok Jin
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Metformin
Lapatinib
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08346-x

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Abstract

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