ERP44 inhibits human lung cancer cell migration mainly via IP3R2

Huang, Xue; Jin, Meng; Chen, Yingxiao; Wang, Jun; Zhai, Kui; Chang, Yan; Yuan, Qi; Yao, Kaitai; Ji, Guangju

doi:10.18632/aging.100984

Cited by 25 publications

(14 citation statements)

References 33 publications

(37 reference statements)

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“…Increased ERp44 expression may be a consequence of high demand in folding of specific proteins or triggered by other stimuli, such as redox status imbalance provoked by 17β-HSD12 silencing. ERp44 knockdown induced apoptosis in HeLa cells, while ERp44 expression inhibited migration in the human non-small lung cancer cell line A549 through a pathway involving inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) [81,82]. Given that the ERp44 increase after 17β-HSD12 downregulation was followed by decreased and increased proliferation/ migration in SUM159 and MDA-MB-231 cells, respectively, it is likely that ERp44 upregulation is an early event following impaired LCFA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Tsachaki

Strauss

Dunkel

et al. 2019

Cell. Mol. Life Sci.

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Metabolic reprogramming of tumor cells involves upregulation of fatty acid (FA) synthesis to support high bioenergetic demands and membrane synthesis. This has been shown for cytosolic synthesis of FAs with up to 16 carbon atoms. Synthesis of long-chain fatty acids (LCFAs), including ω-6 and ω-3 polyunsaturated FAs, takes place at the endoplasmic reticulum. Despite increasing evidence for an important role of LCFAs in cancer, the impact of their synthesis in cancer cell growth has scarcely been studied. Here, we demonstrated that silencing of 17β-hydroxysteroid dehydrogenase type 12 (17β-HSD12), essentially catalyzing the 3-ketoacyl-CoA reduction step in LCFA production, modulates proliferation and migration of breast cancer cells in a cell line-dependent manner. Increased proliferation and migration after 17β-HSD12 knockdown were partly mediated by metabolism of arachidonic acid towards COX2 and CYP1B1-derived eicosanoids. Decreased proliferation was rescued by increased glucose concentration and was preceded by reduced ATP production through oxidative phosphorylation and spare respiratory capacity. In addition, 17β-HSD12 silencing was accompanied by alterations in unfolded protein response, including a decrease in CHOP expression and increase in eIF2α activation and the folding chaperone ERp44. Our study highlights the significance of LCFA biosynthesis for tumor cell physiology and unveils unknown aspects of breast cancer cell heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Tsachaki

Strauss

Dunkel

et al. 2019

Cell. Mol. Life Sci.

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“…Isolated myocytes were used within 8 hours of isolation ( 8 ). To evaluate the role of FBXL2 and IP3R3 in HF diet intake– and FUNDC1 ablation–induced changes in cardiac function, a cohort of cardiomyocytes from WT or FUNDC1 −/− mice was treated with palmitic acid (0.5 mM) ( 8 ) in the absence or presence of the FBXL2 stimulator BC-1258 (10 μg/ml) ( 35 ), the FBXL2 colocalization inhibitor GGTi-2418 (15 μM) ( 22 ), or the IP3R3 inhibitor 2-APB (30 μM) ( 39 ) for 8 hours before the assessment of cardiomyocyte mechanical and mitochondrial properties.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiomyocytes were centrifuged at 800 g for 10 min at room temperature, and cell pellets were resuspended in DMEM containing fetal bovine serum (20%) with 1% penicillin and streptomycin before plating in an uncoated dish for 1 hour at 37°C ( 38 ). To evaluate the role of FBXL2 in HF diet intake–induced changes in mitochondrial integrity and cardiac function, a cohort of cardiomyocytes from WT or FUNDC1 −/− mice was treated with palmitic acid (0.5 mM) ( 8 ) in the absence or presence of the FBXL2 stimulator BC-1258 (10 μg/ml) ( 35 ), the FBXL2 colocalization inhibitor GGTi-2418 (15 μM) ( 22 ), and the IP3R3 inhibitor 2-APB (30 μM) ( 39 ) for 8 hours before the assessment of cardiomyocyte mechanical and mitochondrial properties. To assess the role of FUNDC1 and FBXL2 in palmitic acid–induced responses, adenovirus overexpressing FUNDC1 (sequence, pAdeno-MCMV-Fundc1-3Flag-P2A-EGFP) or FBXL2.…”

Section: Methodsmentioning

confidence: 99%

FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

et al. 2020

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Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca2+ homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1−/− mice accentuated high-fat diet–induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca2+ overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid–induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca2+ homeostasis and cardiac function in obese hearts.

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“…In contrast to the findings which demonstrated that the IP 3 R3/Ca 2+ signalling pathway is critical for cancer invasion and migration in vitro, IP 3 R2 was found to be a key mediator of ER Ca 2+ signals which mediate migration in human lung cancer cells (A549 cell line) [ 30 ].…”

Section: Intracellular Calcium Signalling In Metastasismentioning

confidence: 91%

Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

Alharbi

Zhang

Parrington

2021

Cancers

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Metastatic cancer is one of the major causes of cancer-related mortalities. Metastasis is a complex, multi-process phenomenon, and a hallmark of cancer. Calcium (Ca2+) is a ubiquitous secondary messenger, and it has become evident that Ca2+ signalling plays a vital role in cancer. Ca2+ homeostasis is dysregulated in physiological processes related to tumour metastasis and progression—including cellular adhesion, epithelial–mesenchymal transition, cell migration, motility, and invasion. In this review, we looked at the role of intracellular and extracellular Ca2+ signalling pathways in processes that contribute to metastasis at the local level and also their effects on cancer metastasis globally, as well as at underlying molecular mechanisms and clinical applications. Spatiotemporal Ca2+ homeostasis, in terms of oscillations or waves, is crucial for hindering tumour progression and metastasis. They are a limited number of clinical trials investigating treating patients with advanced stages of various cancer types. Ca2+ signalling may serve as a novel hallmark of cancer due to the versatility of Ca2+ signals in cells, which suggests that the modulation of specific upstream/downstream targets may be a therapeutic approach to treat cancer, particularly in patients with metastatic cancers.

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ERP44 inhibits human lung cancer cell migration mainly via IP3R2

Cited by 25 publications

References 33 publications

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration

FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

Deciphering the Role of Ca2+ Signalling in Cancer Metastasis: From the Bench to the Bedside

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