Long-Term IGF1 Stimulation Leads to Cellular Senescence via Functional Interaction with the Thioredoxin-Interacting Protein, TXNIP

Abstract

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1–TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting.

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

“…Interestingly, the IFN-inducible gene LGALS3BP, previously reported to contribute to EMT and identified in our miRNA resistant network, was predicted by our approach to be associated with senescence escape. On the other hand, TXNIP, another IFN-inducible gene from the miRNA network, recently shown to participate in the induction of senescence upon IGF1 stimulation, was found associated only once and therefore not selected [69]. This further suggests that our approach can relate genes to function beyond their expression pattern, providing a list of 90 genes associated with senescence escape in cancer cells (Fig.…”

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

“…Unexpectedly, IGFBP-3 expression was reduced but was restored by regorafenib in the of βPIX depletion-induced senescence. Long-term treatment with IGF1 also induced senescence accompanied by a reduction in the IGFBP-3 level 54 . Under these conditions, IGFBP-3 may be dispensable for senescence, although deciphering the exact role of the reduced IGFBP-3 expression warrants further study.…”

Aging in the dermis: Fibroblast senescence and its significance

“…Aging‐related reduction in circulating IGF‐1 levels and impaired IGF‐1 signaling likely contribute to the atrophy of skin, muscle, and bone in the elderly (Gallagher & LeRoith, 2011 ). However, long‐term treatment of primary human skin fibroblasts with IGF‐1 induces a premature senescence phenotype (Nagaraj et al., 2022 ; Tran et al., 2014 ). Thus, further studies are needed to elucidate the role of IGF‐1 signaling in dermal aging.…”