Nuclear protein 1 imparts oncogenic potential and chemotherapeutic resistance in cancer

Murphy, Anthony; Costa, Max

doi:10.1016/j.canlet.2020.08.019

Cited by 19 publications

(11 citation statements)

References 63 publications

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“…Importantly, no side effects were observed in these animal models upon ZZW-115 treatment [62]. In addition, NUPR1 can be activated by some anti-cancer agents, thereby conferring drug resistance to the targeted tumors [28]. Depletion of NUPR1 suppressed tumorigenesis and sensitized clear cell renal cell carcinoma to sorafenib treatment in vivo [120].…”

Section: Discussionmentioning

confidence: 91%

“…They have proven useful in overcoming drug resistance and preventing tumor metastasis formation [27], and may represent a promising strategy in combination with other anti-cancer therapies. One important process in cancer cells allowing the formation of drug resistance and heterogeneity is the upregulation of NUPR1 expression [28]. The NUPR1 was recently shown to participate towards iron and energy metabolism and protect cells or tissues against ferroptosis [29,30].…”

Section: Introductionmentioning

confidence: 99%

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NUPR1: A Critical Regulator of the Antioxidant System

Huang

Santofimia‐Castaño

Iovanna

2021

Cancers

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Nuclear protein 1 (NUPR1) is a small intrinsically disordered protein (IDP) activated in response to various types of cellular stress, including endoplasmic reticulum (ER) stress and oxidative stress. Reactive oxygen species (ROS) are mainly produced during mitochondrial oxidative metabolism, and directly impact redox homeostasis and oxidative stress. Ferroptosis is a ROS-dependent programmed cell death driven by an iron-mediated redox reaction. Substantial evidence supports a maintenance role of the stress-inducible protein NUPR1 on cancer cell metabolism that confers chemotherapeutic resistance by upregulating mitochondrial function-associated genes and various antioxidant genes in cancer cells. NUPR1, identified as an antagonist of ferroptosis, plays an important role in redox reactions. This review summarizes the current knowledge on the mechanism behind the observed impact of NUPR1 on mitochondrial function, energy metabolism, iron metabolism, and the antioxidant system. The therapeutic potential of genetic or pharmacological inhibition of NUPR1 in cancer is also discussed. Understanding the role of NUPR1 in the antioxidant system and the mechanisms behind its regulation of ferroptosis may promote the development of more efficacious strategies for cancer therapy.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

NUPR1: A Critical Regulator of the Antioxidant System

Huang

Santofimia‐Castaño

Iovanna

2021

Cancers

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“…Remarkably, the cytotoxic effect of ZZW-115 does not involve nuclear translocation of AIF but it is reversed by the treatment with the NAD + precursor NMN, indicating that the cell death induced by this treatment is, contrary to expected, a non-canonical parthanatos. Importantly, some NUPR1-dependent effects are also involved in the resistance to some anticancer drugs 34 although its molecular explanation remains unknown. Based on our present observations we can hypothesize that during the cellular stress induced in response to the anticancer treatments, the NUPR1 activation could orchestrate a negative feedback with PARP1, limiting the hyperPARylation and its consequent mitochondrial catastrophe-dependent cell death.…”

Section: Discussionmentioning

confidence: 99%

NUPR1 protects against hyperPARylation-dependent cell death

et al. 2022

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Proteomic, cellular and biochemical analysis of the stress protein NUPR1 reveals that it binds to PARP1 into the nucleus and inhibits PARP1 activity in vitro. Mutations on residues Ala33 or Thr68 of NUPR1 or treatment with its inhibitor ZZW-115 inhibits this effect. PARylation induced by 5-fluorouracil (5-FU) treatment is strongly enhanced by ZZW-115 and associated with a decrease of NAD+/NADH ratio and rescued by the PARP inhibitor olaparib. Cell death induced by ZZW-115 treatment of pancreas cancer-derived cells is rescued by olaparib and improved with PARG inhibitor PDD00017273. The mitochondrial catastrophe induced by ZZW-115 treatment or by genetic inactivation of NUPR1 is associated to a hyperPARylation of the mitochondria, disorganization of the mitochondrial network, mitochondrial membrane potential decrease, and with increase of superoxide production, intracellular level of reactive oxygen species (ROS) and cytosolic levels of Ca2+. These features are rescued by olaparib or NAD+ precursor nicotinamide mononucleotide in a dose-dependent manner and partially by antioxidants treatments. In conclusion, inactivation of NUPR1 induces a hyperPARylation, which in turn, induces a mitochondrial catastrophe and consequently a cell death through a non-canonical Parthanatos, since apoptosis inducing-factor (AIF) is not translocated out of the mitochondria.

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“…Several studies have demonstrated that NUPR1 transcriptionally regulates the expression of several drug resistance-associated genes to mediate drug resistance in various malignancies [ 22 , 38 , 44 ]. A previous study reported that NUPR1 mediated sorafenib resistance in hepatocellular carcinoma [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

NUPR1 is a novel potential biomarker and confers resistance to sorafenib in clear cell renal cell carcinoma by increasing stemness and targeting the PTEN/AKT/mTOR pathway

Cheng

Zheng

et al. 2021

Aging

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Background: Sorafenib can improve the survival of metastatic clear cell renal cell carcinoma (ccRCC) patients. However, its benefits are modest, as patients eventually become resistant, and the mechanisms remain elusive. NUPR1, a stress-induced protein, has been reported in malignancies and functions as an oncogene by modulating the stress response, facilitating survival in harsh environments and conferring drug resistance. However, its role in ccRCC has not been explored. Methods: The expression and clinical significance of NUPR1 were analyzed in ccRCC patients in in-house patients and The Cancer Genome Atlas (TCGA) cohorts. The biological functions of NUPR1 were investigated. Xenografts were performed to confirm the effects of NUPR1 on tumorigenesis. The molecular mechanism of NUPR1 was investigated in vitro and in vivo . Results: NUPR1 expression was upregulated in tumor tissue. Further analysis showed that NUPR1 overexpression was associated with an aggressive phenotype and predicted a poor prognosis. Depletion of NUPR1 suppressed tumorigenesis and sensitized cells to sorafenib treatment. Finally, mechanistic investigations indicated that NUPR1 promoted tumorigenesis in ccRCC by increasing stemness and activating the PTEN/AKT/mTOR signaling pathway. Conclusions: Collectively, our results suggest that NUPR1 may serve as a predictor of ccRCC. Notably, NUPR1 silencing reversed sorafenib resistance in ccRCC. These findings provide a novel potential therapeutic target in the clinical management of ccRCC.

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Nuclear protein 1 imparts oncogenic potential and chemotherapeutic resistance in cancer

Cited by 19 publications

References 63 publications

NUPR1: A Critical Regulator of the Antioxidant System

NUPR1: A Critical Regulator of the Antioxidant System

NUPR1 protects against hyperPARylation-dependent cell death

NUPR1 is a novel potential biomarker and confers resistance to sorafenib in clear cell renal cell carcinoma by increasing stemness and targeting the PTEN/AKT/mTOR pathway

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