GOT1 Inhibition Primes Pancreatic Cancer for Ferroptosis through the Autophagic Release of Labile Iron

Kremer, Daniel M.; Nelson, Barbara Scott; Lin, Lin; Yarosz, Emily L; Halbrook, Christopher J.; Kerk, Samuel A.; Sajjakulnukit, Peter; Myers, Amy L.; Thurston, Galloway; Hou, Sean W.; Carpenter, Eileen S.; Andren, Anthony; Nwosu, Zeribe C.; Cusmano, Nicholas; Wisner, Stephanie; Ramos, Johanna; Gao, Ting; Sastra, Stephen A.; Palermo, Carmine F.; Badgley, Michael A.; Zhang, Li; Asara, John M.; Magliano, Marina Pasca di; Shah, Yatrik M.; Crawford, Howard C.; Olive, Kenneth P.; Lyssiotis, Costas A.

doi:10.1101/2020.02.28.970228

Cited by 2 publications

(2 citation statements)

References 54 publications

(102 reference statements)

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“…Kremer et al [60] demonstrated that GOT1 withdrawal was reported to promote a catabolic cell state, resulting in decreased OxPHOS, activated autophagy, and ferritinophagy, which raised iron pools and promoted ferroptosis. Therefore, we assumed that autophagy is related to sepsisinduced ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

et al. 2022

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Sepsis can cause sepsis-associated encephalopathy (SAE), but whether SAE was induced or exacerbated by ferroptosis remains unknown. In this study, the rat sepsis model was constructed using the cecal ligation and puncture method. The blood–brain barrier (BBB) permeability was measured by Evans blue dye (EBD) in vivo. The levels of ROS, Fe ion, MDA, GSH, and GPX4 were assessed by enzyme-linked immunosorbent assay (ELISA). The exosomes isolated from serum were cultured with bEnd.3 cells for the in vitro analysis. Moreover, bEnd.3 cells cultured with 100 μM FeCl3 (iron-rich) were to simulate ferroptosis stress. The cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay. A dual-luciferase reporter gene assay was performed to confirm the relationship between miR-9-5p with NEAT1, TFRC, and GOT1. In vivo, it is found that BBB permeability was damaged in model rats. Level of ROS, Fe ion, and MDA was increased, and level of GSH and GPX4 was decreased, which means ferroptosis was induced by sepsis. Exosome-packaged NEAT1 in serum was significantly upregulated in model rats. In vitro, it is found that NEAT1 functions as a ceRNA for miR-9-5p to facilitate TFRC and GOT1 expression. Overexpression of NEAT1 enhanced ferroptosis stress in bEnd.3 cells. Increased miR-9-5p alleviated sepsis-induced ferroptosis by suppressing the expression of TFRC and GOT1 both in vivo and in vitro. In conclusion, these findings suggest that sepsis induced high expression of serous exosome-derived NEAT1, and it might exacerbate SAE by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis.

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Section: Discussionmentioning

confidence: 99%

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

et al. 2022

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“…Classic examples of this include mitochondrial or DNA damage, such as those induced by chemotherapy and radiotherapy, and more recent nuanced examples illustrate how specific programs can be regulated by autophagy (e.g. iron homeostasis) (Mancias et al 2014;Kremer et al 2020).…”

Section: Cell-intrinsic Metabolic Mechanisms Of Therapeutic Resistancementioning

confidence: 99%

The biological underpinnings of therapeutic resistance in pancreatic cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States and has only recently achieved a 5-yr survival rate of 10%. This dismal prognosis reflects the remarkable capacity of PDAC to effectively adapt to and resist therapeutic intervention. In this review, we discuss recent advances in our understanding of the biological underpinnings of PDAC and their implications as targetable vulnerabilities in this highly lethal disease.

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GOT1 Inhibition Primes Pancreatic Cancer for Ferroptosis through the Autophagic Release of Labile Iron

Abstract: 2 of ferritin. In sum, our study identifies a novel biochemical connection between GOT1, 52iron regulation, and ferroptosis, and suggests the rewired malate-aspartate shuttle plays 53 a role in protecting PDA from severe oxidative challenge. 54 55

Cited by 2 publications

References 54 publications

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis

The biological underpinnings of therapeutic resistance in pancreatic cancer

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