Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3-amplified lung adenocarcinoma cells

Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2023537118. doi: 10.1073/pnas.2023537118.

Abstract

A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIβ (PI4KIIIβ), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3-amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIβ for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIβ antagonist treatment acquire tolerance by activating an miR-218-5p-dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers.

Keywords: Golgi; cancer; lipids; oncogene addiction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors
  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Adenocarcinoma of Lung / genetics*
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 1 / genetics*
  • Enzyme Activation
  • Gene Amplification*
  • Golgi Apparatus / metabolism*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Phosphatidylinositol Phosphates / antagonists & inhibitors
  • Phosphatidylinositol Phosphates / biosynthesis*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / genetics

Substances

  • MIRN218 microRNA, human
  • MicroRNAs
  • Phosphatidylinositol Phosphates
  • RNA, Neoplasm
  • Transforming Growth Factor beta
  • phosphatidylinositol 4-phosphate
  • 1-Phosphatidylinositol 4-Kinase