IGFBP1 Sustains Cell Survival during Spatially-Confined Migration and Promotes Tumor Metastasis

Adv Sci (Weinh). 2023 Jul;10(21):e2206540. doi: 10.1002/advs.202206540. Epub 2023 Jun 9.

Abstract

Cell migration is a pivotal step in metastatic process, which requires cancer cells to navigate a complex spatially-confined environment, including tracks within blood vessels and in the vasculature of target organs. Here it is shown that during spatially-confined migration, the expression of insulin-like growth factor-binding protein 1 (IGFBP1) is upregulated in tumor cells. Secreted IGFBP1 inhibits AKT1-mediated phosphorylation of mitochondrial superoxide dismutase (SOD2) serine (S) 27 and enhances SOD2 activity. Enhanced SOD2 attenuates mitochondrial reactive oxygen species (ROS) accumulation in confined cells, which supports tumor cell survival in blood vessels of lung tissues, thereby accelerating tumor metastasis in mice. The levels of blood IGFBP1 correlate with metastatic recurrence of lung cancer patients. This finding reveals a unique mechanism by which IGFBP1 sustains cell survival during confined migration by enhancing mitochondrial ROS detoxification, thereby promoting tumor metastasis.

Keywords: confined migration; insulin-like growth factor-binding protein 1; mitochondrial reactive oxygen species; superoxide dismutase; tumor metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Lung Neoplasms* / metabolism
  • Mice
  • Phosphorylation
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Insulin-Like Growth Factor Binding Proteins