Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation

Seo, Wonhyoung; Yoo, Seungyeul; Zhong, Yi; Lee, Sang‐Hee; Woo, Soo-Yeon; Choi, Hee-Seon; Won, Minho; Roh, Taylor; Jeon, Sang‐Min; Kim, Kyeong Tae; Silwal, Prashanta; Lee, Min Joung; Heo, Jun Young; Lawlor, Nathan; Kim, Sup; Lee, Dongjun; Kim, Jin Man; Song, Ik‐Chan; Zhu, Jun; Jo, Eun‐Kyeong

doi:10.1186/s13045-022-01372-7

Cited by 8 publications

(4 citation statements)

References 13 publications

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“…The same study further indicated that ERRα plays a crucial role in regulating mtOXPHOS in AML cells. Intervention with XCT-790, an inverse agonist for ERRα, or through gene knockdown led to a decrease in mtOXPHOS activity, enhancing antileukemic responses both in vitro and in vivo [ 65 ]. However, further investigations into ERR are needed to elucidate its role in HM more comprehensively.…”

Section: Nrs In Hmmentioning

confidence: 99%

Exploring the nexus of nuclear receptors in hematological malignancies

Manickasamy,

Sajeev,

BharathwajChetty

et al. 2024

Cell. Mol. Life Sci.

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Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM. Graphical abstract

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Section: Nrs In Hmmentioning

confidence: 99%

Exploring the nexus of nuclear receptors in hematological malignancies

Manickasamy,

Sajeev,

BharathwajChetty

et al. 2024

Cell. Mol. Life Sci.

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“…Thus, it is not surprising that the transcriptional axis PGC-1α/ERRα is upregulated in several cancer cell types and that its inhibition could undermine cell energy production and thus proliferation. Pharmacologic inhibition or genetic ablation of ERRα reduced the proliferation of acute myeloid leukemia cells [106] and glioma cells [107], both in vitro and in vivo. The inhibition of ERRα function, in addition to reducing mitochondrial energy production, also undermines resistance of tumor cells to oxidative stress, by reducing NADPH content as a consequence of impaired glucose/glutamine oxidation [108], and to hypoxia [57].…”

Section: Errα In Tumorsmentioning

confidence: 99%

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

Spinelli,

Bruschi,

Passalacqua

et al. 2024

IJMS

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The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.

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“…Estrogen-related receptor α (ERRα) is an orphan nuclear receptor associated with mitochondrial energy production [ 237 ]. To investigate the regulator of mtOXPHOS in AML and explore its associated treatments, Seo et al [ 238 ]. performed sc-RNA sequencing on primary AML cells from patients as well as in vitro and ex vivo analyses in studying the role of ERRα in regulating mtOXPHOS in AML.…”

Section: Omics Studies In Other Approved Targeted Therapiesmentioning

confidence: 99%

Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia

Zhang,

Huang,

Zhang

et al. 2024

Biomark Res

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Acute myeloid leukemia (AML) is the most frequent leukemia in adults with a high mortality rate. Current diagnostic criteria and selections of therapeutic strategies are generally based on gene mutations and cytogenetic abnormalities. Chemotherapy, targeted therapies, and hematopoietic stem cell transplantation (HSCT) are the major therapeutic strategies for AML. Two dilemmas in the clinical management of AML are related to its poor prognosis. One is the inaccurate risk stratification at diagnosis, leading to incorrect treatment selections. The other is the frequent resistance to chemotherapy and/or targeted therapies. Genomic features have been the focus of AML studies. However, the DNA-level aberrations do not always predict the expression levels of genes and proteins and the latter is more closely linked to disease phenotypes. With the development of high-throughput sequencing and mass spectrometry technologies, studying downstream effectors including RNA, proteins, and metabolites becomes possible. Transcriptomics can reveal gene expression and regulatory networks, proteomics can discover protein expression and signaling pathways intimately associated with the disease, and metabolomics can reflect precise changes in metabolites during disease progression. Moreover, omics profiling at the single-cell level enables studying cellular components and hierarchies of the AML microenvironment. The abundance of data from different omics layers enables the better risk stratification of AML by identifying prognosis-related biomarkers, and has the prospective application in identifying drug targets, therefore potentially discovering solutions to the two dilemmas. In this review, we summarize the existing AML studies using omics methods, both separately and combined, covering research fields of disease diagnosis, risk stratification, prognosis prediction, chemotherapy, as well as targeted therapy. Finally, we discuss the directions and challenges in the application of multi-omics in precision medicine of AML. Our review may inspire both omics researchers and clinical physicians to study AML from a different angle.

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Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation

Cited by 8 publications

References 13 publications

Exploring the nexus of nuclear receptors in hematological malignancies

Exploring the nexus of nuclear receptors in hematological malignancies

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia

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