Abstract
BackgroundInsulin and insulin-like growth factors (IGFs) are key regulators of metabolism and growth. Recent evidences suggest a key role of these pathways in non-classical tissues and the metabolic pathways by which these hormones exert their effects in neoplasia is unclear.AimsTo study insulin/IGFs pathways in drug sensitive and resistant cancer cells representing breast cancer (MCF-7), osteosarcoma (SaOS-2), and ovarian cancer (A2780) and to examine the effect of Sirtuin-7 (Sirt7) inhibition on insulin/IGFs pathways in MCF-7 cell line.MethodsDrug resistant cells were generated by continuous incubation of parental cell lines with stepwise increases in Doxorubicin or Cisplatin over a period of 3 to 6 months. MCF-7 cells were transfected with cloned hairpin siRNA template for Sirt7 using the Amaxa GmbH transfection system. mRNA expression of Sirt7, INSR, IRS-1, IRS-2, IRS-4, IGF-1, IGF-2, MDR-1, MRP-1, BCRP was measured by qPCR and Sirt7 by standard Western blotting. FITC-insulin uptake was imaged with Leica Confocal Microscope.ResultsInsulin receptor (INSR), insulin receptor substrate-1 (IRS-1) were inhibited in drug-induced resistance, whereas IRS-2 was significantly induced in all the chemoresistant cells tested when compared to their parental counterparts. IGF-1 and IGF-2 were also upregulated in all the drug resistant cells tested. Sirt7 was significantly reduced in all chemoresistant cells tested. Knockdown of Sirt7 expression in human breast MCF-7 cell line by siRNA induced premature senescence-like phenotype and multi-drug resistance, suggesting that this gene may play an active role in regulating cancer cell response to stress. Suppression of Sirt7 selectively inhibited INSR and IRS-1, whereas it had minimal effect on that of IRS-2. Sirt7 suppression in MCF-7 also inhibited insulin uptake. Additionally, Sirt7 inhibition upregulated IGF-1, IGF-2 and IGFR expression.ConclusionOur data demonstrate that stress-induced Sirt7 inhibition significantly increases stress resistance and modulates insulin/IGF-1 signaling pathways. More importantly, this study links Sir2 family proteins to insulin/IGF signaling in drug-induced stress resistance in neoplasia.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1135426681234493
Highlights
Insulin and insulin-like growth factors (IGFs) are key regulators of metabolism and growth
Our data demonstrate that stress-induced Sirt7 inhibition significantly increases stress resistance and modulates insulin/IGF-1 signaling pathways
We investigated insulin/IGF pathway in drug-induced resistance and the relationship of Sirt7 to this pathway since it has been shown that reduction in insulin/IGF-1 signaling extends the lifespan of C. elegans, Drosophila and mice [27,28,29,30,31]
Summary
Insulin and insulin-like growth factors (IGFs) are key regulators of metabolism and growth. Recent evidences suggest a key role of these pathways in non-classical tissues and the metabolic pathways by which these hormones exert their effects in neoplasia is unclear. Several recent evidences suggest a key role of these pathways in non-classical tissues It is unclear if these hormones exert their effects in a similar manner in neoplasia. The classical view presents the INSR as being responsible for the metabolic functions and IGF-1R being responsible for the growth, proliferation, protection against apoptosis. These differences may be explained partially by the slight structural differences and tissue distribution; a rational explanation for the divergent biological effects is the interactions with specific substrates. Overexpression of certain IGFBPs, in particular IGFBP2 and IGFBP5, results in increased activity of IGF [23,24]
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