BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism
Luo, Lifang ; Sun, Wenjing ; Zhu, Weijian ; Li, Shuhan ; Zhang, Wenqi ; Xu, Xiaohui ; Fang, Daoquan ; Grahn, Tan Hooi Min LU
; Jiang, Lei
and Zheng, Yihu
(2021)
In Cell Death and Disease
12(2).
- Abstract
Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition,... (More)
Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.
(Less)
- author
- Luo, Lifang
; Sun, Wenjing
; Zhu, Weijian
; Li, Shuhan
; Zhang, Wenqi
; Xu, Xiaohui
; Fang, Daoquan
; Grahn, Tan Hooi Min
LU
; Jiang, Lei
and Zheng, Yihu
- organization
- publishing date
- 2021-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Death and Disease
- volume
- 12
- issue
- 2
- article number
- 169
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:33568627
- scopus:85101029913
- ISSN
- 2041-4889
- DOI
- 10.1038/s41419-021-03456-7
- language
- English
- LU publication?
- yes
- id
- 6b4b9b1c-4264-4ae9-bfba-3cddb8b639f6
- date added to LUP
- 2021-03-02 09:06:14
- date last changed
- 2024-04-18 03:28:10
@article{6b4b9b1c-4264-4ae9-bfba-3cddb8b639f6,
abstract = {{<p>Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.</p>}},
author = {{Luo, Lifang and Sun, Wenjing and Zhu, Weijian and Li, Shuhan and Zhang, Wenqi and Xu, Xiaohui and Fang, Daoquan and Grahn, Tan Hooi Min and Jiang, Lei and Zheng, Yihu}},
issn = {{2041-4889}},
language = {{eng}},
number = {{2}},
publisher = {{Nature Publishing Group}},
series = {{Cell Death and Disease}},
title = {{BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism}},
url = {{http://dx.doi.org/10.1038/s41419-021-03456-7}},
doi = {{10.1038/s41419-021-03456-7}},
volume = {{12}},
year = {{2021}},
}