The strategic involvement of IRS in cancer progression

Ahmed, Mehnaz; Biswas, Tannishtha; Mondal, Susmita

doi:10.1016/j.bbrc.2023.09.036

Cited by 3 publications

References 152 publications

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PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

Wang,

Xu,

Zhang

et al. 2024

Clinical & Translational Med

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BackgroundLiver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline‐5‐carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC.MethodsImmunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony‐forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region.ResultsWe found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression.ConclusionsOur findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.Highlights Pyrroline‐5‐carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells. The expression of PYCR1 in LC is regulated by DNA methylation. Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells. PYCR1 regulates the transcriptional activity of IRS1 by affecting H3K18 lactylation in its promoter region.

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PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

Wang,

Xu,

Zhang

et al. 2024

Clinical & Translational Med

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Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression

Wang,

Lih,

Lee

et al. 2024

Preprint

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In order to advance our understanding of precancers in the pancreas, 69 pancreatic intraductal papillary neoplasms (IPNs), including 64 intraductal papillary mucinous neoplasms (IPMNs) and 5 intraductal oncocytic papillary neoplasms (IOPNs), 32 pancreatic cyst fluid samples, 104 invasive pancreatic ductal adenocarcinomas (PDACs), 43 normal adjacent tissues (NATs), and 76 macro-dissected normal pancreatic ducts (NDs) were analyzed by mass spectrometry. A total of 10,246 proteins and 22,284 glycopeptides were identified in all tissue samples, and 756 proteins with more than 1.5-fold increase in abundance in IPMNs relative to NDs were identified, 45% of which were also identified in cyst fluids. The over-expression of selected proteins was validated by immunolabeling. Proteins and glycoproteins overexpressed in IPMNs included those involved in glycan biosynthesis and the immune system. In addition, multiomics clustering identified two subtypes of IPMNs. This study provides a foundation for understanding tumor progression and targets for earlier detection and therapies.SignificanceThis multilevel characterization of intraductal papillary neoplasms of the pancreas provides a foundation for understanding the changes in protein and glycoprotein expression during the progression from normal duct to intraductal papillary neoplasm, and to invasive pancreatic carcinoma, providing a foundation for informed approaches to earlier detection and treatment.

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Evaluation of the Potential Hypoglycaemic Properties of Mimusops zeyheri Sond. and Aloe marlothii A.Berger, Two Plants Used by Traditional Healers in South Africa

Kamga-Simo,

Kamatou,

Kgopa

et al. 2024

Plants

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Mimusops zeyheri Sond. And Aloe marlothii A.Berger are used traditionally in South Africa to manage many diseases, including diabetes mellitus. The mechanism through which these extracts exert blood glucose lowering is not well understood or reported. This study was aimed at assessing M. zeyheri and A. marlothii plant extracts for their potential to exhibit antidiabetic activity and their associated mechanisms. We evaluated the action of both extracts on major genes involved in the insulin signalling pathways in skeletal muscle cells. The in vitro cytotoxic effects of M. zeyheri and A. marlothii extracts were evaluated using the MTT assay and glucose uptake was evaluated using a glucose oxidase assay. The amount of translocated GLUT-4 was determined using the flow cytometry. Conventional PCR was used to determine the expression of GLUT-1 and GLUT-4 and RT-qPCR. IRS-1 total protein and Phospho-Akt were determined using ELISA. Plant extracts stimulated glucose absorption by skeletal muscle cells. M. zeyheri extract increased glucose absorption in muscle cells after 1 and 3 h of incubation. A 2-fold increase in translocated GLUT-4 was noted with M. zeyheri. The mRNA levels of GLUT-4 and GLUT-1 remained uniform in all treatments, while IRS-1, PI3K, Akt1, Akt2, and PPAR-γ were downregulated by both extracts. The expression of GLUT-4 was significantly increased by the action of insulin and M. zeyheri extract at 500 μg/mL. This study validates the traditional use of aqueous extracts of A. marlothii and M. zeyheri as hypoglycaemic plants and raises the assertion that the selected plant extracts utilise the IRS-1/PI3K/Akt pathway.

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The strategic involvement of IRS in cancer progression

Cited by 3 publications

References 152 publications

PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

PYCR1 promotes liver cancer cell growth and metastasis by regulating IRS1 expression through lactylation modification

Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression

Evaluation of the Potential Hypoglycaemic Properties of Mimusops zeyheri Sond. and Aloe marlothii A.Berger, Two Plants Used by Traditional Healers in South Africa

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