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.
Lei Shi  1 ,  Xiaochao Tan  1 ,  Xin Liu  1 ,  Jiang Yu  1 ,  Neus Bota-Rabassedas  1 ,  Yichi Niu  2  3 ,  Jiayi Luo  2  4 ,  Yuanxin Xi  5 ,  Chenghang Zong  2 ,  Chad J Creighton  5  6  7 ,  Jeffrey S Glenn  8  9 ,  Jing Wang  5 ,  Jonathan M Kurie  10
Affiliations
  • 1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
  • 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
  • 3. Genetics and Genomics Graduate Program, Baylor College of Medicine, Houston, TX 77030.
  • 4. Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, TX 77030.
  • 5. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
  • 6. Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
  • 7. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030.
  • 8. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
  • 9. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
  • 10. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; [email protected].
PMID: 34155143 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.
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