Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

Radde, Brandie N.; Ivanova, Margarita; Xuan, Huy; Alizadeh-Rad, Negin; Piell, Kellianne M.; Hoose, Patrick Van; Cole, Marsha P.; Muluhngwi, Penn; Kalbfleisch, Theodore S.; Rouchka, Eric C.; Hill, Bradford G.; Klinge, Carolyn M.

doi:10.1016/j.yexcr.2016.08.006

Cited by 40 publications

(25 citation statements)

References 42 publications

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“…Our findings show that the expression level of BAX/BCL2 was significantly increased in NRF1 silenced LGCs. This is consistent with a previous study, which found that NRF1 silence stimulated MCF-7 breast cancer cell apoptosis (Radde et al 2016). Consequently, the change in mRNA ratio of BAX/BCL2 could destabilize mitochondria, lead to CYCS release from mitochondria to cytoplasm and induce caspases activation (Raisova et al 2001).…”

Section: Discussionsupporting

confidence: 91%

Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells

et al. 2017

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During goat follicular development, abnormal expression of nuclear respiratory factor 1 () in granulosa cells may drive follicular atresia with unknown regulatory mechanisms. In this study, we investigated the effects of on steroidogenesis and cell apoptosis by overexpressing or silencing it in goat luteinized granulosa cells (LGCs). Results showed that knockdown of expression significantly inhibited the expression of and, which are involved in sex steroid hormones synthesis, and led to lower estrogen levels. Knockdown of resulted in an increased percentage of apoptosis, probably due to the release of cytochrome c from mitochondria, accompanied by upregulating mRNA and protein levels of apoptosis-related markers BAX, caspase 3 and caspase 9. These data indicate that might be related with steroidogenesis and cell apoptosis. Furthermore, silence reduced mitochondrial transcription factor A () transcription activity, mtDNA copy number and ATP level. Simultaneously, knockdown of suppressed the transcription and translation levels of SOD, GPx and CAT, decreased glutathione level and increased 8-OHdG level. However, the overexpression of in LGCs or gain of in silenced LGCs increased the expression of genes involved in mitochondrial function and biogenesis, and elevated the antioxidant stress system and steroids synthesis. Taken together, aberrant expression of could induce mitochondrial dysfunction and disturb the cellular redox balance, which lead to disturbance of steroid hormone synthesis, and trigger LGC apoptosis through the mitochondria-dependent pathway. These findings will be helpful for understanding the role of in goat ovarian follicular development and atresia.

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Section: Discussionsupporting

confidence: 91%

Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells

et al. 2017

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“…This was evidenced by, 1) activation of ERK resulted in transcriptional activation of the -272/-191 fragment of the CD47 promoter; 2) this fragment is enriched of consensus binding sites for NRF-1; 3) NRF-1 binds to this fragment that was enhanced by BRAF/MEK inhibitors; 4) knockdown of NRF-1 abolished ERK-mediated upregulation of CD47; In addition, the role of NRF-1 in ERK-mediated CD47 upregulation is supported by the finding that ERK signalling promotes NRF-1 expression. The physiological role of NRF-1 is regulation of transcription of nuclear-encoded mitochondrial genes and thus mediates the biogenomic coordination between nuclear and mitochondrial genomes [ 44 , 45 ]. Its activation involves phosphorylation and relocation from the cytoplasm to the nucleus [ 44 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma

et al. 2017

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The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy.

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“…Inhibiting glycolysis via hexokinase II inhibition decreased Akt/mTOR/HIF-1α signaling and restored Tamoxifen sensitivity in antiestrogen-resistant breast cancer cells [237]. A study corroborating an increase in glycolysis in TAM-R cells also observed a counter intuitive increase in NRF-1 and its target TFAM [238]. Similarly, RNA sequencing studies to identify genes differentially expressed in tamoxifen-resistant vs. -sensitive cells found gene expression pattern suggesting dysfunctional mitochondria and altered OXPHOS in TAM-R cells [239].…”

Section: Effects Of Treatment and Resistance To Soc On Metabolic Rmentioning

confidence: 99%

Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications

Gandhi

Das

2019

Cells

161

132

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Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.

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Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

Cited by 40 publications

References 42 publications

Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells

Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells

BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma

Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications

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