Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L)

Exp Cell Res. 2004 Aug 15;298(2):329-38. doi: 10.1016/j.yexcr.2004.04.031.

Abstract

Lats2, also known as Kpm, is the second mammalian member of the novel Lats tumor suppressor gene family. Recent studies have demonstrated that Lats2 negatively regulates the cell cycle by controlling G1/S and/or G2/M transition. To further understand the role of Lats2 in the control of human cancer development, we have expressed the protein in human lung cancer cells by transduction of a replication-deficient adenovirus expressing human Lats2 (Ad-Lats2). Using a variety of techniques, including Annexin V uptake, cleavage of PARP, and DNA laddering, we have demonstrated that the ectopic expression of human Lats2 induced apoptosis in two lung cancer cell lines, A549 and H1299. Caspases-3, 7, 8, and 9 were processed in the Ad-Lats2-transduced cells; however, it was active caspase-9, not caspase-8, that initiated the caspase cascade. Inhibitors specific to caspase-3 and 9 delayed the onset of Lats2-mediated apoptosis. Western blot analysis revealed that anti-apoptotic proteins, BCL-2 and BCL-x(L), but not the pro-apoptotic protein, BAX, were downregulated in Ad-Lats2-transduced human lung cancer cells. Overexpression of either Bcl-2 or Bcl-x(L) in these cells lead to the suppression of Lats2-mediated caspase cleavage and apoptosis. These results show that Lats2 induces apoptosis through downregulating anti-apoptotic proteins, BCL-2 and BCL-x(L), in human lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5 / metabolism
  • Apoptosis / genetics*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line, Tumor
  • DNA Damage / genetics
  • Down-Regulation / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genetic Vectors
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • bcl-X Protein

Substances

  • Annexin A5
  • BCL2L1 protein, human
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • bcl-X Protein
  • LATS2 protein, human
  • Protein-Serine-Threonine Kinases
  • CASP9 protein, human
  • Caspase 9
  • Caspases