Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis

Carcinogenesis. 2012 Feb;33(2):301-11. doi: 10.1093/carcin/bgr287. Epub 2011 Dec 9.

Abstract

Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apc(min/+) mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apc(min/+)/TR3(-/-) mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Checkpoint Kinase 2
  • Cisplatin / pharmacology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / prevention & control
  • Gene Knockdown Techniques / methods
  • HEK293 Cells
  • Humans
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / prevention & control*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transplantation, Heterologous / methods

Substances

  • Antineoplastic Agents
  • BABAM2 protein, human
  • Nerve Tissue Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • RNA, Messenger
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cisplatin