Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer

Abstract

Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

“…In mammals, the PI3K-Akt-mTOR pathway has been reported to regulate autophagy through the insulin receptor IGF-1 [51]. Additionally, activation of insulin like growth factor 1 receptor (IGF-1R) signaling could be suppressing the autophagic lysosomal pathway [52]. The key components of insulin receptor substrate 1 (IRS1), an adaptor of IGF1R, are involved in IGF-1 signaling pathways.…”

Body Mass Index and Colorectal Cancer

“…Insulin is an anabolic hormone which coordinates glucose to either oxidation to provide energy or storage in the body after uptake in insulin-sensitive cells [45]. Insulin receptors (IRs) exist in IR-A, IR-B and IR-related receptor (IRR) isoforms and insulin has been shown also to have tumorigenic effects on preneoplastic cells which have insulin receptors [46,47]. IRs and IGF receptors have an extracellular ligand-binding domain and an intracellular protein kinase domain.…”

“…IRs and IGF receptors have an extracellular ligand-binding domain and an intracellular protein kinase domain. IGF-1 and insulin-like growth factor-2 (IGF-2) are mitogenic growth factors [46]. They have also metabolic functions.…”

“…IGF receptors include IGF1R and IGF2R [48]. The binding of insulin and/or IGF ligands to cell surface receptors on cancer cells results in cell proliferation and survival [46,49]. Upregulation of the IR and IGF1R has been demonstrated in human breast cancer and prostate cancer, respectively [50,51].…”

Tumor Biological Aspects of a Large-Scale Retrospective Study: The Role of Tumor Cell Heterogeneity, Inflammation and Aging in Survival

“…The complexity of the insulin-like growth factor (IGF)/ IGF-receptor 1 (IGF1R) pathway and the autophagy machinery may partly account for this failure. 10 Recent data suggest that inhibition of IGF/IGF1R system along with manipulation of the autophagy process could play an important role in suppressing MetS-related inflammatory and cancerous disorders of the colon. 10 On the other hand, IGF1R inhibition may lead to a decrease in mTORC2 (mammalian target of rapamycin complex 2) function, which, in turn, reduces the activity of protein kinase C α and β, and so, affects the autophagosome formation by modulating the cytoskeleton and the rate of endocytosis.…”