Knockdown of PRL-3 increases mitochondrial superoxide anion production through transcriptional regulation of RAP1

Yang, Yongyong; Lian, Shenyi; Meng, Lin; Tian, Zhihua; Feng, Qin; Wang, Yue; Wang, Ping; Qu, Like; Shou, Chengchao

doi:10.2147/cmar.s165344

Cited by 3 publications

(5 citation statements)

References 42 publications

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“…The large influence of PRL-3 on protein expression could lead to the suspicion that it acts as a transcription factor, and this was reported in a recent paper. 64 In summary, this study establishes a role for PRL-3 as an important regulator of metabolism in cancer cells of hematological origin. Most notably, PRL-3 promotes the serine/glycine pathway and induces aerobic glycolysis, the latter partly through upregulation of glycolytic enzymes and GLDC, but independently of HIF-1α, c-Myc, and AMPK.…”

Section: Discussionsupporting

confidence: 52%

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Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

et al. 2021

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Cancer cells often depend on microenvironment signals from molecules such as cytokines for proliferation and metabolic adaptations. PRL‐3, a cytokine‐induced oncogenic phosphatase, is highly expressed in multiple myeloma cells and associated with poor outcome in this cancer. We studied whether PRL‐3 influences metabolism. Cells transduced to express PRL‐3 had higher aerobic glycolytic rate, oxidative phosphorylation, and ATP production than the control cells. PRL‐3 promoted glucose uptake and lactate excretion, enhanced the levels of proteins regulating glycolysis and enzymes in the serine/glycine synthesis pathway, a side branch of glycolysis. Moreover, mRNAs for these proteins correlated with PRL‐3 expression in primary patient myeloma cells. Glycine decarboxylase (GLDC) was the most significantly induced metabolism gene. Forced GLDC downregulation partly counteracted PRL‐3‐induced aerobic glycolysis, indicating GLDC involvement in a PRL‐3‐driven Warburg effect. AMPK, HIF‐1α, and c‐Myc, important metabolic regulators in cancer cells, were not mediators of PRL‐3’s metabolic effects. A phosphatase‐dead PRL‐3 mutant, C104S, promoted many of the metabolic changes induced by wild‐type PRL‐3, arguing that important metabolic effects of PRL‐3 are independent of its phosphatase activity. Through this study, PRL‐3 emerges as one of the key mediators of metabolic adaptations in multiple myeloma.

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Section: Discussionsupporting

confidence: 52%

“…Clearly, a phosphatase‐dead PRL‐3 mutant has important biological effects like those of WT PRL‐3. The large influence of PRL‐3 on protein expression could lead to the suspicion that it acts as a transcription factor, and this was reported in a recent paper 64 …”

Section: Discussionmentioning

confidence: 93%

Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

et al. 2021

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“…In metastatic CRC cell lines, the inhibition of SIRT3 using shRNAs has been found to lead to a decrease in both PGC1α mRNA and protein levels ( 26 ). Additionally, oncogenic phosphatase PRL3, a regulator of reactive oxygen species (ROS), has been found to exert its influence on upregulated PGC1α expression through the mediation of Ras-proximate-1(RAP1) ( 27 ). However, in specific scenarios where CRC cells are quiescent, the level of PGC1α has been found to be reduced.…”

Section: Roles Of Pgc1α In Cancer Cellsmentioning

confidence: 99%

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

Wang,

Peng,

Yang

et al. 2024

Front. Oncol.

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PGC1α, a central player in mitochondrial biology, holds a complex role in the metabolic shifts seen in cancer cells. While its dysregulation is common across major cancers, its impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas in others, overexpression escalates respiration and aggression. PGC1α’s interactions with distinct signaling pathways and transcription factors further diversify its roles, often in a tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1α-targeted approaches. This review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1α in diverse cancers. We examined PGC1α’s tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator. In cancers where PGC1α is tumor-suppressive, reinstating its levels could halt cell proliferation and invasion, and make the cells more receptive to chemotherapy. In cancers where the opposite is true, halting PGC1α’s upregulation can be beneficial as it promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype. Thus, to target PGC1α effectively, understanding its nuanced role in each cancer subtype is indispensable. This can pave the way for significant strides in the field of oncology.

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Section: Cellular Functions Regulated By Prl3mentioning

confidence: 99%

“…In addition, a study found that PRL3 knockdown promotes production of mitochondrial superoxide anion with a concomitant increase in mitochondrial membrane potential and induction of cell cycle arrest 101 . PRL3 acts as a transcription factor, binding to the promoter of repressor activator protein 1 (RAP1), a protein that regulates the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) 101 . Thus, knockdown of PRL3 decreases PGC-1α as well as its downstream genes superoxide dismutase 2 (SOD2) and uncoupling protein 2 (UCP2), both reactive oxygen species (ROS)-detoxifying proteins that prevent the accumulation of ROS.…”

Section: Cellular Functions Regulated By Prl3mentioning

confidence: 99%

PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types

Chia¹,

Ang²,

Thura³

et al. 2023

Theranostics

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Phosphatase of Regenerating Liver-3 (PRL3) was discovered in 1998 and was subsequently found to be correlated with cancer progression and metastasis in 2001. Extensive research in the past two decades has produced significant findings on PRL3-mediated cancer signaling and functions, as well as its clinical relevance in diverse types of cancer. PRL3 has been established to play a role in many cancer-related functions, including but not limited to metastasis, proliferation, and angiogenesis. Importantly, the tumor-specific expression of PRL3 protein in multiple cancer types has made it an attractive therapeutic target. Much effort has been made in developing PRL3-targeted therapy with small chemical inhibitors against intracellular PRL3, and notably, the development of PRL3-zumab as a novel cancer immunotherapy against PRL3. In this review, we summarize the current understanding of the role of PRL3 in cancer-related cellular functions, its prognostic value, as well as perspectives on PRL3 as a target for unconventional immunotherapy in the clinic with PRL3-zumab.

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Knockdown of PRL-3 increases mitochondrial superoxide anion production through transcriptional regulation of RAP1

Cited by 3 publications

References 42 publications

Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types

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