Rethinking the Relationship between Insulin and Cancer

Vigneri, Riccardo; Sciacca, Laura; Vigneri, Paolo

doi:10.1016/j.tem.2020.05.004

“…This association is especially well described for postmenopausal luminal BC but has also been observed for other BC subtypes regardless of the menopausal status 3 – 6 . Several potential mechanisms linking obesity and cancer have been identified as for instance higher estrogen exposure 7 , 8 , systemic low-grade inflammation 9 , 10 , increased insulin and insulin-like growth factor expression 11 , 12 or altered adipokines secretion 13 , 14 . Obese patients have increased circulating levels of apelin 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients

Gourgue

¹

,

Derouane

²

,

Marcke

³

et al. 2021

Sci Rep

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Obesity is a known factor increasing the risk of developing breast cancer and reducing disease free survival. In addition to these well-documented effects, recent studies have shown that obesity is also affecting response to chemotherapy. Among the multiple dysregulations associated with obesity, increased level of the apelin adipokine has been recently shown to be directly involved in the association between obesity and increased breast cancer progression. In this study, we analyzed in a retrospective cohort of 62 breast cancer patients the impact of obesity and tumoral apelin expression on response to neoadjuvant chemotherapy. In the multivariate logistic regression, obesity and high tumoral apelin expression were associated with a reduced response to NAC in our cohort. However, obesity and high tumoral apelin expression were not correlated, suggesting that those two parameters could be independently associated with reduced NAC response. These findings should be confirmed in independent cohorts.

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“…Coupling nutrient inputs to cellular metabolism, survival and growth is intrinsically dependent upon Insulin signalling (IS). Hypo-and hyper-activation of IS leads to various patho-physiologies including diabetes, accelerated aging and cancer, which are attributed to under-or over-phosphorylation of certain IS components (Arcidiacono et al, 2012;Guo, 2014;Hill and Milner, 1985;Shimobayashi et al, 2018;Shoelson et al, 2006;Vigneri et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin signaling (IS), an evolutionarily conserved mechanism is essential for cellular/organismal metabolism and growth (Boucher et al, 2014;Haeusler et al, 2018;Saltiel and Kahn, 2001). Aberrant IS is associated both causally and consequentially with growth abnormalities, inflammation, accelerated aging and diseases including metabolic disorders and cancer (Arcidiacono et al, 2012;Guo, 2014;Hill and Milner, 1985;Shimobayashi et al, 2018;Shoelson et al, 2006;Vigneri et al, 2020). Genetic perturbations and omics-based studies have elucidated importance of key phosphorylation events in response to insulin stimulation (Humphrey et al, 2015;Krüger et al, 2008;Schmelzle et al, 2006;Yugi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Continuous variable response, kinetic gating and connectivity that determine topology of insulin signaling are perturbed in hyper-insulinemic states

Shukla

¹

,

Kadam

²

,

Padinhateeri

³

et al. 2020

Preprint

0

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Understanding kinetic control of biological processes is as important as identifying components that constitute pathways. Insulin signaling (IS) is central for almost all metazoans and its perturbations are associated with various diseases and aging. While temporal phosphorylation changes and kinetic constants have provided some insights, constant or variable parameters that establish and maintain signal topology are poorly understood. Our iterative experimental and mathematical simulation-based approaches reveal novel kinetic parameters of IS that encode concentration and nutrient dependent information. Further, we find that pulsatile fasting insulin rewires IS akin to memory and in anticipation of a fed response. Importantly, selective kinetic gating of signals and maximum connectivity, between metabolic and growth-factor arms under normo-insulinemic states, maintains network topology. In addition to unraveling kinetic constraints that determine cascade architecture, our findings will help in identifying novel therapeutic strategies that conserve coupling between metabolic and growth-factor arms, which is lost in diseases and conditions of hyperinsulinemia.

show abstract

“…Coupling nutrient inputs to cellular metabolism, survival and growth is intrinsically dependent upon Insulin signalling (IS). Hypo-and hyper-activation of IS leads to various patho-physiologies including diabetes, accelerated aging and cancer, which are attributed to under-or over-phosphorylation of certain IS components (Arcidiacono et al, 2012;Guo, 2014;Hill and Milner, 1985;Shimobayashi et al, 2018;Shoelson et al, 2006;Vigneri et al, 2020). Despite this our ability to tweak the cascade to restore balance between metabolic and mitogenic arms has been limited by paucity of information vis-à-vis parameters that govern network topology.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin signaling (IS), an evolutionarily conserved mechanism is essential for cellular/organismal metabolism and growth (Boucher et al, 2014;Haeusler et al, 2018;Saltiel and Kahn, 2001). Aberrant IS is associated both causally and consequentially with growth abnormalities, inflammation, accelerated aging and diseases including metabolic disorders and cancer (Arcidiacono et al, 2012;Guo, 2014;Hill and Milner, 1985;Shimobayashi et al, 2018;Shoelson et al, 2006;Vigneri et al, 2020). Genetic perturbations and omics-based studies have elucidated importance of key phosphorylation events in response to insulin stimulation (Humphrey et al, 2015;Krüger et al, 2008;Schmelzle et al, 2006;Yugi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Continuous variable response, kinetic gating and connectivity that govern IS topology are perturbed in hyperinsulinemia

Shukla

¹

,

Kadam

²

,

Padinhateeri

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Understanding kinetic control of biological processes is as important as identifying components that constitute pathways. Insulin-signaling (IS) is central for almost all metazoans and its perturbations are associated with various diseases and aging. While temporal phosphorylation changes and kinetic constants have provided some insights, constant or variable parameters that establish and maintain signal topology are poorly understood. Our iterative experimental and mathematical simulation-based approaches reveal novel kinetic parameters that encode concentration and nutrient dependent information. Further, we find that pulsatile fasting insulin rewires IS akin to memory and in anticipation of a fed response. Importantly, selective kinetic gating of signals and maximum connectivity, between metabolic and growth-factor arms under normo-insulinemic states, maintains network topology. In addition to unraveling kinetic constraints that determine cascade architecture, our findings will help in identifying novel therapeutic strategies that conserve coupling between metabolic and growth-factor arms, which is lost in diseases and conditions of hyperinsulinemia.

show abstract

Rethinking the Relationship between Insulin and Cancer

Cited by 49 publications

References 75 publications

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients

Continuous variable response, kinetic gating and connectivity that determine topology of insulin signaling are perturbed in hyper-insulinemic states

Continuous variable response, kinetic gating and connectivity that govern IS topology are perturbed in hyperinsulinemia

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