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Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells.

Abstract
Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1(-/-) mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1(+/+) MEFs, whereas CDK10 protein was downregulated in the rescued Pin1(-/-) MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and Tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
AuthorsP Khanal, H J Yun, S C Lim, S G Ahn, H E Yoon, K W Kang, R Hong, H S Choi
JournalOncogene (Oncogene) Vol. 31 Issue 34 Pg. 3845-56 (Aug 23 2012) ISSN: 1476-5594 [Electronic] England
PMID22158035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Hormonal
  • NIMA-interacting peptidylprolyl isomerase
  • Ubiquitin
  • Tamoxifen
  • Proto-Oncogene Proteins c-raf
  • CDK10 protein, human
  • Cyclin-Dependent Kinases
  • Peptidylprolyl Isomerase
Topics
  • Animals
  • Antineoplastic Agents, Hormonal (pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms (genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Cyclin-Dependent Kinases (genetics, metabolism)
  • Drug Resistance, Neoplasm (genetics)
  • Embryo, Mammalian (cytology)
  • Fibroblasts (cytology, drug effects, metabolism)
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Peptidylprolyl Isomerase (genetics, metabolism)
  • Phosphorylation (drug effects)
  • Protein Binding
  • Proteolysis
  • Proto-Oncogene Proteins c-raf (metabolism)
  • RNA Interference
  • Tamoxifen (pharmacology)
  • Ubiquitin (metabolism)

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