Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells

J Cell Sci. 2018 Aug 16;131(16):jcs216408. doi: 10.1242/jcs.216408.

Abstract

Metastasis of breast cancer cells to distant organs is responsible for ∼50% of breast cancer-related deaths in women worldwide. SHIP2 (also known as INPPL1) is a phosphoinositide 5-phosphatase for phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2]. Here we show, through depletion of SHIP2 in triple negative MDA-MB-231 cells and the use of SHIP2 inhibitors, that cell migration appears to be positively controlled by SHIP2. The effect of SHIP2 on migration, as observed in MDA-MB-231 cells, appears to be mediated by PI(3,4)P2. Adhesion on fibronectin is always increased in SHIP2-depleted cells. Apoptosis measured in MDA-MB-231 cells is also increased in SHIP2-depleted cells as compared to control cells. In xenograft mice, SHIP2-depleted MDA-MB-231 cells form significantly smaller tumors than those formed by control cells and less metastasis is detected in lung sections. Our data reveal a general role for SHIP2 in the control of cell migration in breast cancer cells and a second messenger role for PI(3,4)P2 in the migration mechanism. In MDA-MB-231 cells, SHIP2 has a function in apoptosis in cells incubated in vitro and in mouse tumor-derived cells, which could account for its role on tumor growth determined in vivo.

Keywords: Breast cancer cell; Cell migration; Phosphoinositide; SHIP2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / pathology*
  • Cell Movement / drug effects*
  • Cell Movement / genetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / antagonists & inhibitors*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • INPPL1 protein, human
  • Inppl1 protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases