Dataset Information

Progerin modulates the IGF-1R/Akt signaling involved in aging.

ABSTRACT: Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24^-/- mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA-associated progeroid disorders.

SUBMITTER: Jiang B

PROVIDER: S-EPMC9269893 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Progerin modulates the IGF-1R/Akt signaling involved in aging.

Jiang Bo B Wu Xuan X Meng Fang F Si Limiao L Cao Sunrun S Dong Yuqing Y Sun Huayi H Lv Mengzhu M Xu Hongde H Bai Ning N Guo Qiqiang Q Song Xiaoyu X Yu Yang Y Guo Wendong W Yi Fei F Zhou Tingting T Li Xiaoman X Feng Yanling Y Wang Zhuo Z Zhang Dan D Guan Yi Y Ma Mengtao M Liu Jingwei J Li Xining X Zhao Weidong W Liu Baohua B Finkel Toren T Cao Liu L

Science advances 20220708 27

Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24-/- mice, a mouse model of progeria. Mechanistically, progerin misloc ...[more]

PMID: 35857466

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Project description:Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric α2β2 receptor, in which the α subunits comprise the ligand binding site, whereas the β subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the α (aa 1-524) and β (aa 741-936) subunits, and found that either dnIGF1Rα and/or dnIGF1Rβ effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1Rα and/or dnIGF1Rβ inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1Rα. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1Rα, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

Dataset Information

Progerin modulates the IGF-1R/Akt signaling involved in aging.

Publications

Progerin modulates the IGF-1R/Akt signaling involved in aging.

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