Doxycyclin ameliorates a starvation-induced germline tumor in C. elegans daf-18/PTEN mutant background

Exp Gerontol. 2014 Aug;56:114-22. doi: 10.1016/j.exger.2014.04.002. Epub 2014 Apr 15.

Abstract

Managing available resources is a key necessity of each organism to cope with the environment. The nematode C. elegans responds to nutritional deprivation or harsh environmental conditions with a multitude of developmental adaptations, among them a starvation-induced quiescence at early larval development (L1). daf-18, the C. elegans homolog of the human tumor suppressor gene PTEN, is essential for the maintenance of survival and germline stem cell arrest during the L1 diapause. We show here that daf-18 mutants, independently to their failure to maintain G2 arrest of the primordial germ cells, develop a gonad phenotype after refeeding. This highly penetrant gonadal phenotype is further enhanced by a mutation in shc-1, encoding a protein homologous to the human adaptor ShcA. Features of this phenotype are a tumor-like phenotype encompassing hyper-proliferation of germ cell nuclei and disruption/invasion of the basement membrane surrounding the gonad. The penetrance of this phenotype is reduced by decreasing starvation temperature. In addition, it is also ameliorated in a dose-dependent way by exposure to the antibiotic doxycyclin either during starvation or during subsequent refeeding. Since, in eukaryotic cells, doxycyclin specifically blocks mitochondrial translation, our results suggest that daf-18 and shc-1;daf-18 mutants fail to adapt mitochondrial activity to reduced nutritional availability during early larval developing.

Keywords: Doxycyclin; Metabolic rate; Mitochondria; Tumor; daf-18/PTEN; shc-1/ShcA.

Publication types

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

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Dose-Response Relationship, Drug
  • Doxycycline / pharmacology*
  • Energy Metabolism / drug effects
  • Food Deprivation*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Genotype
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutation*
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Neoplasms, Germ Cell and Embryonal / prevention & control*
  • Nutritional Status
  • Phenotype
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism
  • Temperature
  • Time Factors

Substances

  • Anticarcinogenic Agents
  • Caenorhabditis elegans Proteins
  • DAF-18 protein, C elegans
  • Shc Signaling Adaptor Proteins
  • Doxycycline