The role of branched chain amino acids metabolic disorders in tumorigenesis and progression

Wang, Jingtong; Wang, Wei; Zhu, Feng; Duan, Qiuhong

doi:10.1016/j.biopha.2022.113390

Cited by 15 publications

(9 citation statements)

References 177 publications

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“…BCAT1 is a cytosolic enzyme located on chromosome 12p12.1, which could catalyze the synthesis of α‐ketoglutarates from branched‐chain amino acids and then produce glutamates and branched‐chain α‐ketoacids. [ 30 ] Lin et al [ 31 ] showed that BCAT1 is highly expressed in non‐small cell lung cancer and facilitates cell proliferation and invasion by activating the Wnt/Myc signaling. Wei et al [ 32 ] reported that GAS6‐AS2 upregulated BCAT1 expression by sponging miR‐934, thereby promoting the proliferation, migration, and invasion of OS cells.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Li,

Meng,

Liu

et al. 2023

J Biochem & Molecular Tox

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Increasing evidence indicated that protein arginine methyltransferase‐1 (PRMT1) is an oncogene in multiple malignant tumors, including osteosarcoma (OS). The aim of this study was to investigate the underlying mechanism of PRMT1 in OS. The effects of PRMT1 or BCAT1, branched‐chain amino acid transaminase 1 (BCAT1) on OS cell proliferation, invasion, autophagy, and apoptosis in vitro were examined. Moreover, molecular control of PRMT1 on c‐Myc or transactivation of BCAT1 on c‐Myc was assessed by chromatin immunoprecipitation and quantitative reverse transcription PCR assays. The effects of PRMT1 in vivo were examined with a xenograft tumor model. The results showed that PRMT1 was potently upregulated in OS tissues and cells. Upregulation of PRMT1 markedly increased OS cell proliferation and invasion in vitro and reduced cell apoptosis, whereas PRMT1 silencing showed the opposite effects. Cisplatin, one of the most effective chemotherapeutic drugs, improved cell survival rate by inducing the expression of PRMT1 to downregulate the cisplatin sensitivity. Meanwhile, the cisplatin‐induced upregulation of PRMT1 expression caused dramatically autophagy induction and autophagy‐mediated apoptosis by inactivating the mTOR signaling pathway, which could be reversed by 3‐methyladenine, an autophagy inhibitor, or PRMT1 silencing. PRMT1 could activate c‐Myc transcription and increase c‐Myc‐mediated expression of BCAT1. Furthermore, BCAT1 overexpression counteracted the effects of PRMT1 knockdown on cell proliferation, invasion, and apoptosis. Of note, deficiency of PRMT1 suppressed tumor growth in vivo. PRMT1 facilitated the proliferation and invasion of OS cells, inhibited cell apoptosis, and decreased chemotherapy sensitivity through c‐Myc/BCAT1 axis, which may become potential target in treating OS.

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Section: Discussionmentioning

confidence: 99%

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Li,

Meng,

Liu

et al. 2023

J Biochem & Molecular Tox

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“…As discussed in the introduction, BCAA metabolism and BCKDK itself are deregulated in cancer and emerging as a potential new target in cancer. Thus, BCKDKi may also be useful as single agents or combined with other drugs targeting metabolism [ 54 , 55 ]. Some cancers, including ovarian and breast, show alterations in BCAA metabolism that may render them sensitive to BCKDKi.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of branched-chain alpha-keto acid dehydrogenase kinase augments the sensitivity of ovarian and breast cancer cells to paclitaxel

et al. 2022

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Context Many cancer patients who initially respond to chemotherapy eventually develop chemoresistance, and to address this, we previously conducted a RNAi screen to identify genes contributing to resistance. One of the hits from the screen was branched-chain α-keto acid dehydrogenase kinase (BCKDK). BCKDK controls the metabolism of branched-chain amino acids (BCAAs) through phosphorylation and inactivation of the branched-chain α-keto acid dehydrogenase complex (BCKDH), thereby inhibiting catabolism of BCAAs. Methods We measured the impact on paclitaxel sensitivity of inhibiting BCKDK in ovarian and breast cancer cell lines. Results Inhibition of BCKDK using siRNA or two chemical inhibitors (BCKDKi) was synergistic with paclitaxel in both breast and ovarian cancer cells. BCKDKi reduced levels of BCAA and the addition of exogenous BCAA suppressed this synergy. BCKDKi inactivated the mTORC1-Aurora pathway, allowing cells to overcame M-phase arrest induced by paclitaxel. In some cases, cells almost completed cytokinesis, then reverted to a single cell, resulting in multinucleate cells. Conclusion BCKDK is an attractive target to augment the sensitivity of cancer cells to paclitaxel.

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“…Additionally, the enhanced catabolism of branched-chain amino acids (BCAAs), facilitated by BCAT1, is implicated in promoting bone metastasis by sustaining energy supply and activating stemness-related pathways [ 135 ]. BCAAs serve as both carbon and nitrogen sources for energy production, nucleotide synthesis, and protein synthesis [ 140 ]. Their metabolism is disrupted in multiple tumors, often associated with alterations in enzymes, transporters, and transcription factors involved in the BCAA metabolic pathway.…”

Section: Altered Metabolism In Bone Metastasismentioning

confidence: 99%

Bridging the Gap in Understanding Bone Metastasis: A Multifaceted Perspective

Elaasser,

Arakil,

Mohammad

2024

IJMS

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The treatment of patients with advanced cancer poses clinical problems due to the complications that arise as the disease progresses. Bone metastases are a common problem that cancer patients may face, and currently, there are no effective drugs to treat these individuals. Prostate, breast, and lung cancers often spread to the bone, causing significant and disabling health conditions. The bone is a highly active and dynamic tissue and is considered a favorable environment for the growth of cancer. The role of osteoblasts and osteoclasts in the process of bone remodeling and the way in which their interactions change during the progression of metastasis is critical to understanding the pathophysiology of this disease. These interactions create a self-perpetuating loop that stimulates the growth of metastatic cells in the bone. The metabolic reprogramming of both cancer cells and cells in the bone microenvironment has serious implications for the development and progression of metastasis. Insight into the process of bone remodeling and the systemic elements that regulate this process, as well as the cellular changes that occur during the progression of bone metastases, is critical to the discovery of a cure for this disease. It is crucial to explore different therapeutic options that focus specifically on malignancy in the bone microenvironment in order to effectively treat this disease. This review will focus on the bone remodeling process and the effects of metabolic disorders as well as systemic factors like hormones and cytokines on the development of bone metastases. We will also examine the various therapeutic alternatives available today and the upcoming advances in novel treatments.

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The role of branched chain amino acids metabolic disorders in tumorigenesis and progression

Cited by 15 publications

References 177 publications

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Knockdown of PRMT1 suppresses the malignant biological behavior of osteosarcoma cells and increases cisplatin sensitivity via c‐Myc‐mediated BCAT1 downregulation

Inhibition of branched-chain alpha-keto acid dehydrogenase kinase augments the sensitivity of ovarian and breast cancer cells to paclitaxel

Bridging the Gap in Understanding Bone Metastasis: A Multifaceted Perspective

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