Cited by 288PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerCancer, Hypoxia, and Metabolism

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Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer

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Hopkins, Benjamin D., Goncalves, Marcus D., Cantley, Lewis C.·2020·Nature Reviews Endocrinology

DOI 10.1038/s41574-020-0329-9PMC PMC7286536

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Abstract

Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin-PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer.

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Authors: Hopkins, B. D., Goncalves, M. D., & Cantley, L. C.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Weill Cornell Medicine (US)
Corresponding author: Hopkins, Benjamin D.
ORCID: Hopkins, Benjamin D.
Goncalves, Marcus D.
Cantley, Lewis C.
Venue: Nature Reviews Endocrinology
Publisher: Springer Science and Business Media LLC
Published: 2020-03-03
Volume: 16
Issue: 5
Pages: 276-283
ISSN: 1759-5029 (ISSN-L)
1759-5037
DOI: 10.1038/s41574-020-0329-9
PMC: PMC7286536
OpenAlex: W3009258273
Cited by: 288
References: 78
Citations by year: 2026: 34 · 2025: 50 · 2024: 46 · 2023: 52 · 2022: 45 · 2021: 41 · 2020: 20
FWCI: 3.81
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Endocrinology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (K08CA230318, R00CA230384, R35CA197588)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: insulin signaling, PI3K signaling, mTOR, oncogenic transformation, cancer metabolism, insulin resistance, insulin receptor, cancer therapy resistance, metabolic targeting, tumor initiation
MeSH terms: Animals, Endocrine System, Biological Evolution, Humans, Insulin, Neoplasms, Signal Transduction, Phosphatidylinositol 3-Kinases

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Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer

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