Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

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.

Key points

  • Systemic factors such as insulin activate the same signalling pathways as some of the most recurrent mutations in human cancer.

  • The phosphoinositide 3-kinase (PI3K) signalling cascade, which is activated by insulin, regulates cellular metabolism and cell fate decisions, including cell survival and proliferation.

  • High insulin levels can promote and sustain tumour growth.

  • Therapeutic targeting of the PI3K signalling cascade is subject to a variety of cellular and systemic feedback mechanisms, including acute insulin release.

  • Therapeutic approaches that reduce insulin exposure might increase the efficacy of agents that target the PI3K signalling axis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Insulin regulates glycolysis through both AKT-dependent and AKT-independent mechanisms.
Fig. 2: Tissue and tumour response to insulin signalling.
Fig. 3: Analysis of the frequency of mutations in insulin–PI3K signalling.
Fig. 4: Mechanisms to inhibit insulin feedback in tumours.

Similar content being viewed by others

References

  1. Karamitsos, D. T. The story of insulin discovery. Diabetes Res. Clin. Pract. 93, S2–S8 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Banting, F. G. & Best, C. H. Pancreatic Extracts (Toronto Univ. Library, 1922).

  3. Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8, 915–928 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Dong, M. Q. et al. Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. Science 317, 660–663 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  7. White, M. F. & Kahn, C. R. The insulin signaling system. J. Biol. Chem. 269, 1–4 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Ruderman, N. B., Kapeller, R., White, M. F. & Cantley, L. C. Activation of phosphatidylinositol 3-kinase by insulin. Proc. Natl Acad. Sci. USA 87, 1411–1415 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, N. et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363, 85–88 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Simon, M. A., Dodson, G. S. & Rubin, G. M. An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell 73, 169–177 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Gallagher, E. J. & LeRoith, D. Minireview: IGF, insulin, and cancer. Endocrinology 152, 2546–2551 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Engelman, J. A. & Cantley, L. C. Chemoprevention meets glucose control. Cancer Prev. Res. 3, 1049–1052 (2010).

    Article  CAS  Google Scholar 

  14. Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shaham, O. et al. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol. Syst. Biol. 4, 214 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cheng, Z., Tseng, Y. & White, M. F. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol. Metab. 21, 589–598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yaribeygi, H., Farrokhi, F. R., Butler, A. E. & Sahebkar, A. Insulin resistance: review of the underlying molecular mechanisms. J. Cell Physiol. 234, 8152–8161 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Rinderknecht, E. & Humbel, R. E. Polypeptides with nonsuppressible insulin-like and cell-growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and II. Proc. Natl Acad. Sci. USA 73, 2365–2369 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pollak, M. The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin. Cancer Res. 18, 40–50 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Cignarelli, A. et al. Insulin and insulin receptors in adipose tissue development. Int. J. Mol. Sci. 20, E759 (2019).

    Article  PubMed  CAS  Google Scholar 

  21. Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cao, X., Kambe, F., Moeller, L. C., Refetoff, S. & Seo, H. Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol. Endocrinol. 19, 102–112 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Saad, M. J. et al. Modulation of early steps in insulin action in the liver and muscle of epinephrine treated rats. Endocrine 3, 755–759 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Deibert, D. C. & DeFronzo, R. A. Epinephrine-induced insulin resistance in man. J. Clin. Invest. 65, 717–721 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tan, J. et al. PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy. Cancer Discov. 3, 1156–1171 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Cunningham, J. T. & Ruggero, D. New connections between old pathways: PDK1 signaling promotes cellular transformation through PLK1-dependent MYC stabilization. Cancer Discov. 3, 1099–1102 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Hu, H. et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164, 433–446 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Khayat, Z. A. et al. Insulin-induced actin filament remodeling colocalizes actin with phosphatidylinositol 3-kinase and GLUT4 in L6 myotubes. J. Cell Sci. 113, 279–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Hopkins, B. D., Hodakoski, C., Barrows, D., Mense, S. M. & Parsons, R. E. PTEN function: the long and the short of it. Trends Biochem. Sci. 39, 183–190 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hopkins, B. D. et al. A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341, 399–402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hodakoski, C. et al. Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc. Natl Acad. Sci. USA 111, 155–160 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Hodakoski, C., Fine, B., Hopkins, B. & Parsons, R. Analysis of intracellular PTEN signaling and secretion. Methods 77–78, 164–171 (2015).

    Article  PubMed  CAS  Google Scholar 

  33. Fine, B. et al. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325, 1261–1265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lyssenko, V., Groop, L. & Prasad, R. B. Genetics of type 2 diabetes: it matters from which parent we inherit the risk. Rev. Diabet. Stud. 12, 233–242 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hopkins, B. D., Goncalves, M. D. & Cantley, L. C. Obesity and cancer mechanisms: cancer metabolism. J. Clin. Oncol. 34, 4277–4283 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martinez-Lopez, A. et al. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clin. Genet. 91, 14–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  38. Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat. Genet. 26, 379–382 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C. & Cantley, L. C. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell Biol. 25, 1596–1607 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brachmann, S. M. et al. Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement. Mol. Cell Biol. 25, 2593–2606 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Luo, J. et al. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab. 3, 355–366 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Shaw, R. J. & Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424–430 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Dibble, C. C. & Cantley, L. C. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 25, 545–555 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956).

    Article  CAS  PubMed  Google Scholar 

  48. Orgel, E. & Mittelman, S. D. The links between insulin resistance, diabetes, and cancer. Curr. Diab. Rep. 13, 213–222 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Novosyadlyy, R. et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 70, 741–751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Andre, F. et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380, 1929–1940 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Saura, C. et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 20, 1226–1238 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Goncalves, M. D., Hopkins, B. D. & Cantley, L. C. Dietary fat and sugar in promoting cancer development and progression. Annu. Rev. Cancer Biol. 3, 255–273 (2019).

    Article  Google Scholar 

  56. Momcilovic, M. et al. The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma. Cancer Cell 33, 905–921.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rozengurt, E., Soares, H. P. & Sinnet-Smith, J. Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol. Cancer Ther. 13, 2477–2488 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Buck, E. et al. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. Mol. Cancer Ther. 9, 2652–2664 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Shirakawa, J. et al. Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, beta-cell functions, and beta-cell proliferation in male mice. Endocrinology 155, 2102–2111 (2014).

    Article  PubMed  CAS  Google Scholar 

  60. Iams, W. T. & Lovly, C. M. Molecular pathways: clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clin. Cancer Res. 21, 4270–4277 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Osborne, C. K., Bolan, G., Monaco, M. E. & Lippman, M. E. Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc. Natl Acad. Sci. USA 73, 4536–4540 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Goodwin, P. J. et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol. 20, 42–51 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Ma, J. et al. Prediagnostic body mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 9, 1039–1047 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dearth, R. K., Cui, X., Kim, H. J., Hadsell, D. L. & Lee, A. V. Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle 6, 705–713 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Gallagher, E. J. et al. Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. Oncogene 31, 3213–3222 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Bendell, J. C. et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Goncalves, M. D., Hopkins, B. D. & Cantley, L. C. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N. Engl. J. Med. 379, 2052–2062 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. Neal, E. G. et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500–506 (2008).

    Article  PubMed  Google Scholar 

  69. Kennedy, A. R. et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol. Metab. 292, E1724–E1739 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Douris, N. et al. Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet. Biochim. Biophys. Acta 1852, 2056–2065 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nasiri, A. R., Rodrigues, M. R., Li, Z., Leitner, B. P. & Perry, R. J. SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia. Cancer Metab. 7, 10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Loves, S. et al. Effects of diazoxide-mediated insulin suppression on glucose and lipid metabolism in nondiabetic obese men. J. Clin. Endocrinol. Metab. 103, 2346–2353 (2018).

    Article  PubMed  Google Scholar 

  73. Loves, S. et al. High-dose, diazoxide-mediated insulin suppression boosts weight loss induced by lifestyle intervention. J. Clin. Endocrinol. Metab. 103, 4014–4022 (2018).

    Article  PubMed  Google Scholar 

  74. Shams-White, M. M. et al. Operationalizing the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations: a standardized scoring system. Nutrients 11, 1572 (2019).

    Article  PubMed Central  Google Scholar 

  75. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the National Cancer Institute of the National Institutes of Health as research reported in this publication was supported under award numbers R35CA197588 (L.C.C.), R00CA230384 (B.D.H.) and K08CA230318 (M.D.G.). The authors would also like to acknowledge the support of the Grey Foundation’s Basser Initiative (L.C.C. and B.D.H.), a generous gift from The Roger and Susan Hertog Charitable Fund (L.C.C.) and the Lung Cancer Research Foundation (M.D.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or these foundations.

Author information

Authors and Affiliations

Authors

Contributions

B.D.H. and M.D.G. researched data for the article, contributed to discussion of its content, wrote the article and reviewed and edited the manuscript before submission. L.C.C. contributed to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Benjamin D. Hopkins.

Ethics declarations

Competing interests

B.D.H., M.D.G. and L.C.C. are all founders of and consultants for Faeth, a company developing nutrition for cancer care. L.C.C. is a founder and member of the scientific advisory board and board of directors of Agios and Petra Pharma, which are companies developing drugs to target metabolism.

Additional information

Peer review information

Nature Reviews Endocrinology thanks F. Janku and the other, anonymous, reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related link

The Cancer Genome Atlas (TCGA): https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hopkins, B.D., Goncalves, M.D. & Cantley, L.C. Insulin–PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol 16, 276–283 (2020). https://doi.org/10.1038/s41574-020-0329-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-020-0329-9

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer