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LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216569 | GEO | 2023/03/10

REPOSITORIES: GEO

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LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [lncRNA]

Project description:To explore the critical non-coding RNAs in the regulation of ferroptosis, we treated panc-1 with cystine depletion.We then performed gene expression profiling analysis using data obtained from RNA-seq of panc-1 cultured normally and panc-1 treated with cystine depletion for 24h in triplicate.

2023-03-10 | GSE216567 | GEO

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [circRNA]

2023-03-10 | GSE216566 | GEO

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [miRNA-seq]

2023-03-10 | GSE216568 | GEO

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex

Project description:LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex

| PRJNA894229 | ENA

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [circRNA]

Project description:LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [circRNA]

| PRJNA894231 | ENA

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [lncRNA]

Project description:LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [lncRNA]

| PRJNA894233 | ENA

LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [miRNA-seq]

Project description:LINC01133 can induce acquired resistance to ferroptosis in pancreatic cancer by enhancing the mRNA stability of FSP1 through forming the LINC01133-FUS-FSP1 complex [miRNA-seq]

| PRJNA894232 | ENA

Phase separation of FSP1 promotes ferroptosis.

Project description:Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.

| S-EPMC10338336 | biostudies-literature

ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability.

Project description:Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains cell survival and promotes cancer metastasis in cancer cells. Ferroptosis is a type of cell necrosis caused by an overload of lipid oxidation, which has been demonstrated to be involved in cancer cell metastasis. However, the mechanism by which fatty acid metabolism regulates the anti-ferroptosis signaling pathways is not fully understood. The formation of ovarian cancer spheroids helps to counteract the hostile microenvironment of the peritoneal cavity with low oxygen, shortage of nutrients, and subjected to platinum therapy. Previously, we demonstrated that Acyl-CoA synthetase long-chain family member 1 (ACSL1) promotes cell survival and peritoneal metastases in ovarian cancer, but the mechanism is still not well elucidated. In this study, we demonstrate that the formation of spheroids and under exposure to platinum chemotherapy increased the levels of anti-ferroptosis proteins as well as ACSL1. Inhibition of ferroptosis can enhance spheroid formation and vice versa. Genetic manipulation of ACSL1 expression showed that ACSL1 reduced the level of lipid oxidation and increased the resistance to cell ferroptosis. Mechanistically, ACSL1 increased the N-myristoylation of ferroptosis suppressor 1 (FSP1), resulting in the inhibition of its degradation and translocation to the cell membrane. The increase in myristoylated FSP1 functionally counteracted oxidative stress-induced cell ferroptosis. Clinical data also suggested that ACSL1 protein was positively correlated with FSP1 and negatively correlated with the ferroptosis markers 4-HNE and PTGS2. In conclusion, this study demonstrated that ACSL1 enhances antioxidant capacity and increases ferroptosis resistance by modulating the myristoylation of FSP1.

| S-EPMC9992462 | biostudies-literature

Structural insights into FSP1 catalysis and ferroptosis inhibition.

Project description:Ferroptosis suppressor protein 1 (FSP1, also known as AIMF2, AMID or PRG3) is a recently identified glutathione-independent ferroptosis suppressor1-3, but its underlying structural mechanism remains unknown. Here we report the crystal structures of Gallus gallus FSP1 in its substrate-free and ubiquinone-bound forms. The structures reveal a FAD-binding domain and a NAD(P)H-binding domain, both of which are shared with AIF and NADH oxidoreductases4-9, and a characteristic carboxy-terminal domain as well. We demonstrate that the carboxy-terminal domain is crucial for the catalytic activity and ferroptosis inhibition of FSP1 by mediating the functional dimerization of FSP1, and the formation of two active sites located on two sides of FAD, which are responsible for ubiquinone reduction and a unique FAD hydroxylation respectively. We also identify that FSP1 can catalyze the production of H2O2 and the conversion of FAD to 6-hydroxy-FAD in the presence of oxygen and NAD(P)H in vitro, and 6-hydroxy-FAD directly inhibits ferroptosis in cells. Together, these findings further our understanding on the catalytic and ferroptosis suppression mechanisms of FSP1 and establish 6-hydroxy-FAD as an active cofactor in FSP1 and a potent radical-trapping antioxidant in ferroptosis inhibition.

| S-EPMC10516921 | biostudies-literature

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