Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells

Biochem Pharmacol. 2003 Jul 1;66(1):93-103. doi: 10.1016/s0006-2952(03)00248-x.

Abstract

Gossypol, a male contraceptive drug, has been demonstrated to have antiproliferative and antimetastatic effects on many kinds of cancer cells in vitro. HT-29 human carcinoma cell line is one of the most susceptible cell lines to gossypol-induced cell death. Here, it is shown that treatment of HT-29 cells with gossypol not only induces cell cycle arrest on the G0/G1 phase, but also induces apoptosis. With a serial of Western blot analysis, it is revealed that gossypol-induced cell cycle arrest is involved in P21 up-regulation and cyclin D1 down-regulation; gossypol-induced apoptosis triggers down-regulation of anti-apoptosis Bcl-2 members: Bcl-X(L), Bag-1 and Mcl-1, up-regulation of pro-apoptosis Bcl-2 member Bak, activation of caspase-3, -6, -7, -8, and -9, up-regulation of Apaf-1, release of cytochrome c (cyto-c) from mitochondria, and activation of both DFF45 and PARP. Taken together, gossypol-induced cell death initiates extensive alterations of cell cycle and apoptosis proteins. Gossypol-induced apoptosis of HT-29 cells is through first the mitochondrial pathway, then the death receptor pathway, and the mitochondria pathway is, at least in part, involved in cyto-c release.

MeSH terms

  • Apoptosis*
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Death
  • Colonic Neoplasms / pathology
  • Cyclin D1 / metabolism
  • Cytochrome c Group / metabolism
  • Enzyme Activation
  • Gossypol / pharmacology*
  • HT29 Cells
  • Humans
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Cytochrome c Group
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • caspase-activated DNase inhibitor
  • Cyclin D1
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • Gossypol