Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in human lung adenocarcinoma

Elife. 2020 Sep 29:9:e58108. doi: 10.7554/eLife.58108.

Abstract

Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however, whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). COX6B2 is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD+ generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor-specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.

Keywords: COX6B2; cancer biology; cancer testes antigen; cytochrome c oxidase; human; lung cancer; oxidative phosphorylation.

Publication types

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

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Animals
  • Cell Proliferation / genetics*
  • Cell Survival / genetics*
  • Electron Transport Complex IV / genetics*
  • Electron Transport Complex IV / metabolism
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / genetics*
  • Mice
  • Mice, Nude
  • Oxidative Phosphorylation*

Substances

  • COX6B1 protein, human
  • Electron Transport Complex IV