Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Kalakonda, Sudhakar; Nallar, Shreeram C.; Jaber, Sausan; Keay, Susan; Rorke, Ellen A.; Munivenkatappa, Raghava; Lindner, Daniel J.; Fiskum, Gary; Kalvakolanu, Dhananjaya V.

doi:10.1073/pnas.1303760110

Cited by 31 publications

(42 citation statements)

References 97 publications

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“…To date, three biological STAT3 inhibitors including suppressor of cytokine signaling 3 (SOCS3) [39, 40, 42], protein inhibitor of activated STAT3 (PIAS3) [41, 42], and GRIM-19 [26–29, 42] have been reported. However, tumor-suppressive roles of SOCS3 and PIAS3 have not yet been established [42]. It is therefore of interest in our current study to focus on the role of GRIM-19 in gastric carcinogenesis and its correlation with STAT3 activation in GC cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, pharmacological inhibition of STAT3 did not completely abrogate GRIM-19 loss-driven tumorigenesis, suggesting that the full capacity of GRIM-19 loss to tumor growth may extend beyond its ability to activate STAT3. Since GRIM-19 loss also contributed to the switch between oxidative and glycolytic pathways [36, 42, 43], while aberrant glycolytic metabolism provides tumor growth advantages [44–46]. Therefore, compensatory activation of these contributions by GRIM-19 loss may provide a reasonable account for the GRIM-19 loss-driven tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

Huang

Yang

et al. 2016

Oncotarget

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Aberrant STAT3 activation occurs in most human gastric cancers (GCs) and contributes to the malignant progression of GC, but mechanism(s) underlying aberrant STAT3 remain largely unknown. Here we demonstrated that the gene associated with retinoid interferon-induced mortality 19 (GRIM-19) was severely depressed or lost in GC and chronic atrophic gastritis (CAG) tissues and its loss contributed to GC tumorigenesis partly by activating STAT3 signaling. In primary human GC tissues, GRIM-19 was frequently depressed or lost and this loss correlated with advanced clinical stage, lymph node metastasis, H. pylori infection and poor overall survival of GC patients. In CAG tissues, GRIM-19 was progressively decreased along with its malignant transformation. Functionally, we indentified an oncogenic role of GRIM-19 loss in promoting GC tumorigenesis. Ectopic GRIM-19 expression suppressed GC tumor formation in vitro and in vivo by inducing cell cycle arrest and apoptosis. Moreover, we revealed that GRIM-19 inhibited STAT3 transcriptional activation and its downstream targets by reducing STAT3 nuclear distribution. Conversely, knockdown of GRIM-19 induced aberrant STAT3 activation and accelerated GC cell growth in vitro and in vivo, and this could be partly attenuated by the blockage of STAT3 activation. In addition, we observed subcellular redistributions of GRIM-19 characterized by peri-nuclear aggregates, non-mitochondria cytoplasmic distribution and nuclear invasion, which should be responsible for reduced STAT3 nuclear distribution. Our studies suggest that mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for GC development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of GC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

Huang

Yang

et al. 2016

Oncotarget

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“…Even, a mono-allelic loss was sufficient for tumor development. A significant decline of mitochondrial electron transport machinery viz., RC-2, RC-4 (cytochrome’c oxidase) and RC-5 (ATP synthase) and a modest increase in RC-3 (cytochrome’c reductase) levels occurred in the absence of GRIM-19 [118]. These are consistent with a strong decline in oxygen consumption in these cells.…”

Section: The Mitochondrial Function Of Grim-19mentioning

confidence: 61%

“…We have shown that conditional deletion of Grim-19 in adult mouse skin does not cause significant lethality. However, these mice are highly prone to chemically-induced tumor development [118]. Even, a mono-allelic loss was sufficient for tumor development.…”

Section: The Mitochondrial Function Of Grim-19mentioning

confidence: 99%

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GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism

Nallar

Kalvakolanu

2017

Cytokine & Growth Factor Reviews

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Cytokines induce cell proliferation or growth suppression depending on the context. It is increasingly becoming clear that success of standard radiotherapy and/or chemotherapeutics to eradicate solid tumors is dependent on IFN signaling. In this review we discuss the molecular mechanisms of tumor growth suppression by a gene product isolated in our laboratory using a genome-wide expression knock-down strategy. Gene associated with retinoid-IFN-induced mortality −19 (GRIM-19) functions as non-canonical tumor suppressor by antagonizing oncoproteins. As a component of mitochondrial respiratory chain, GRIM-19 influences the degree of “Warburg effect” in cancer cells as many advanced and/or aggressive tumors show severely down-regulated GRIM-19 levels. In addition, GRIM-19 appears to regulate innate and acquired immune responses in mouse models. Thus, GRIM-19 is positioned at nodes that favor cell protection and/or prevent aberrant cell growth.

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Mitochondrial GRIM-19 deficiency facilitates gastric cancer metastasis through oncogenic ROS-NRF2-HO-1 axis via a NRF2-HO-1 loop

Wang

Xue

et al. 2020

Gastric Cancer

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Background NRF2, a prime target of cellular defense against oxidative stress, has shown a dark side profile in cancer progression. GRIM-19, an essential subunit of the mitochondrial MRC complex I, was recently identified as a suppressive role in tumorigenesis of human gastric cancer (GC). However, little information is available on the role of GRIM-19 and its cross-talk with NRF2 in GC metastasis. Methods Online GC database was used to investigate DNA methylation and survival outcomes of GRIM-19. CRISPR/Cas9 lentivirus-mediated gene editing, metastasis mice models and pharmacological intervention were applied to investigate the role of GRIM-19 deficiency in GC metastasis. Quantitative RT-PCR, FACS, Western blot, IHC, IF and reporter gene assay were performed to explore underlying mechanisms. Results Low GRIM-19 is correlated with poor survival outcome of GC patients while DNA hypermethylation is associated with GRIM-19 downregulation. GRIM-19 deficiency facilitates GC metastasis and triggers aberrant oxidative stress as well as ROS-dependent NRF2-HO-1 activation. Experimental interventions of specific ROS, NRF2 or HO-1 inhibitor significantly abrogate GRIM-19 deficiency-driven GC metastasis in vitro and in vivo. Moreover, HO-1 inhibition not only reverses GRIM-19 deficiency-driven NRF2 activation, but also feedback blocks NRF2 activator-induced NRF2 signaling, resulting in decreased metastasis-associated genes. Conclusions Our data suggest that GRIM-19 deficiency accelerates GC metastasis through the oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into the role of oncogenic NRF2 in tumor progression, but also provides new strategies to alleviate the dark side of NRF2 by targeting HO-1.

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Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice

Cited by 31 publications

References 97 publications

Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism

Mitochondrial GRIM-19 deficiency facilitates gastric cancer metastasis through oncogenic ROS-NRF2-HO-1 axis via a NRF2-HO-1 loop

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