LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis

Cancer Res. 2008 Jan 1;68(1):55-63. doi: 10.1158/0008-5472.CAN-07-3225.

Abstract

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.

Publication types

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

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • AMP-Activated Protein Kinases
  • Animals
  • Carcinogens / toxicity*
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Epidermis / drug effects
  • Epidermis / pathology
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Mutant Strains
  • Neoplasms, Squamous Cell / chemically induced
  • Neoplasms, Squamous Cell / genetics*
  • Neoplasms, Squamous Cell / pathology
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Retinoblastoma Protein / antagonists & inhibitors
  • Retinoblastoma Protein / metabolism
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Carcinogens
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • 9,10-Dimethyl-1,2-benzanthracene
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinases