Arginine inhibits the malignant transformation induced by interferon-gamma through the NF-κB-GCN2/eIF2α signaling pathway in mammary epithelial cells in vitro and in vivo

Ren, Wenbo; Yang, Li; Xia, Xiaojing; Guo, Wenfei; Zhai, Taiyu; Jin, Yuting; Che, Yuanyuan; Gao, Haidi; Duan, Xiumei; Ma, Haiying; Huang, Tung Po; Huang, Jing; Lei, Liancheng

doi:10.1016/j.yexcr.2018.05.003

Cited by 15 publications

(18 citation statements)

References 61 publications

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“…In previous studies, we found that IFN-γ induces the malignant transformation of BMECs by GCN2, a nutrient receptor (Xia et al, 2016b;Ren et al, 2018). However, among the phenotypes of the malignant transformation, including cell cycle shortening, increased cell proliferation, and the occurrence of cell migration and invasion, the abnormal regulation of cell growth is the first step in cell malignant transformation.…”

Section: Discussionmentioning

confidence: 94%

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Ren

Xia

Huang

et al. 2019

J. Zhejiang Univ. Sci. B

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Interferon-γ (IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.

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Section: Discussionmentioning

confidence: 94%

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Ren

Xia

Huang

et al. 2019

J. Zhejiang Univ. Sci. B

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“…Activating transcription factor 4 (ATF4) is a stress-induced transcription factor regulating a wide variety of genes involved in cellular adaptation to unfavorable growth conditions, such as ER stress resulting from unfold protein response (UPR) and the amino acid response (AAR). ATF4 is activated in response to each of Pro [103], Gln [23,33], Asn [73] and Arg starvations [104], following the conserved AAR signal of GCN2-p-eIF2-ATF4. However, ATF4 is also a target of c-Myc via GCN2 kinase [97] (Figure 3), indicating the cross-talk between two important transcriptional regulation pathways in general amino acid starvation response.…”

Section: Atf4mentioning

confidence: 99%

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

et al. 2021

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Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.

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“…The PKR/eIF2α-P displays anti-tumor effects and can suppress HER2+ BC growth in mice [26] (Figure 1). Trastuzumab can induce the PKR/eIF2α-P and its downstream anti-tumor pathways, in sensitive but not resistant HER2+ BC.…”

Section: Eukaryotic Translation Initiation Factor 2 (Eif2)mentioning

confidence: 99%

“…Subsequently, Ren et al reported that, on account of arginine addition, eIF2α was involved in the inhibition of malignant transformation of mammary epithelial cells. The NF-κB-GCN2/eIF2α pathway can alleviate malignant transformation in IFN-γ-induced mammary epithelial cells through reducing the ability of cell proliferation, migration and colony formation [26].…”

Section: Eukaryotic Translation Initiation Factor 2 (Eif2)mentioning

confidence: 99%

“…SAL003 can improve the efficiency of Trastuzumab, and Trastuzumab can stimulate PKR [25]. eIF2α-p leads to an inhibition of the translation initiation [26] and can inhibit HER2+. Stress induces the expression of X-box binding protein 1 (XBP1) of the unfolded protein response (UPR) [29], by phosphorylating eIF2α, which results in protein refolding and degradation.…”

Section: Eukaryotic Translation Initiation Factor 2 (Eif2)mentioning

confidence: 99%

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Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

Chen

Yang

Naß

et al. 2020

Cancers

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Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC.

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Arginine inhibits the malignant transformation induced by interferon-gamma through the NF-κB-GCN2/eIF2α signaling pathway in mammary epithelial cells in vitro and in vivo

Cited by 15 publications

References 61 publications

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate

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