LncRNA CamK-A Regulates Ca 2+-Signaling-Mediated Tumor Microenvironment Remodeling

Mol Cell. 2018 Oct 4;72(1):71-83.e7. doi: 10.1016/j.molcel.2018.08.014. Epub 2018 Sep 13.

Abstract

Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca2+) flux and Ca2+-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically, CamK-A activates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.

Keywords: Ca(2+); LncRNA; NF-κB; PDX; cancer; glycolysis; metabolism; signal transduction; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Signaling / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • NF-kappa B / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phosphorylation
  • RNA, Long Noncoding / genetics*
  • Signal Transduction / genetics
  • Tumor Microenvironment / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • NF-kappa B
  • RNA, Long Noncoding
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • PNCK protein, human