p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy

Cancer Cell. 2002 Jun;1(5):493-503. doi: 10.1016/s1535-6108(02)00068-5.

Abstract

Chemotherapeutic agents simultaneously induce transcription factors p53 and NFkappaB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFkappaB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2(-/-) MEFs, which lack detectable NFkappaB activity. Compared to WT fibroblasts, IKK1/2(-/-) fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IkappaBalphaM, implying a role for NFkappaB in blocking chemotherapy-induced p53 and cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / physiology*
  • Cell Line
  • Down-Regulation
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Enzyme Stability
  • Fibroblasts / cytology
  • I-kappa B Kinase
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Nuclear Proteins*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • RNA, Messenger / metabolism
  • Retroviridae
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation

Substances

  • Antibiotics, Antineoplastic
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse