Rnai screening identifies tak1 as a potential target for the enhanced efficacy of topoisomerase inhibitors

S. E. Martin, Zhaohui Wu, K. Gehlhaus, T. L. Jones, Y. W. Zhang, R. Guha, S. Miyamoto, Y. Pommier, N. J. Caplen

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

In an effort to develop strategies that improve the efficacy of existing anticancer agents, we have conducted a siRNA-based RNAi screen to identify genes that, when targeted by siRNA, improve the activity of the topoisomerase I (Top1) poison camptothecin (CPT). Screening was conducted using a set of siRNAs corresponding to over 400 apoptosisrelated genes in MDA-MB-231 breast cancer cells. During the course of these studies, we identified the silencing of MAP3K7 as a significant enhancer of CPT activity. Follow-up analysis of caspase activity and caspase-dependent phosphorylation of histone H2AX demonstrated that the silencing of MAP3K7 enhanced CPT-associated apoptosis. Silencing MAP3K7 also sensitized cells to additional compounds, including CPT clinical analogs. This activity was not restricted to MDA-MB-231 cells, as the silencing of MAP3K7 also sensitized the breast cancer cell line MDA-MB-468 and HCT-116 colon cancer cells. However, MAP3K7 silencing did not affect compound activity in the comparatively normal mammary epithelial cell line MCF10A, as well as some additional tumorigenic lines. MAP3K7 encodes the TAK1 kinase, an enzyme that is central to the regulation of many processes associated with the growth of cancer cells (e.g. NF-κB, JNK, and p38 signaling). An analysis of TAK1 signaling pathway members revealed that the silencing of TAB2 also sensitizes MDA-MB-231 and HCT-116 cells towards CPT. These findings may offer avenues towards lowering the effective doses of Top1 inhibitors in cancer cells and, in doing so, broaden their application.

Original languageEnglish (US)
Pages (from-to)976-986
Number of pages11
JournalCurrent Cancer Drug Targets
Volume11
Issue number8
DOIs
StatePublished - Oct 1 2011

Fingerprint

Topoisomerase Inhibitors
Camptothecin
Caspases
Small Interfering RNA
Breast Neoplasms
HCT116 Cells
Cell Line
Type I DNA Topoisomerase
Poisons
RNA Interference
Antineoplastic Agents
Histones
Colonic Neoplasms
Genes
Neoplasms
Breast
Phosphotransferases
Epithelial Cells
Phosphorylation
Apoptosis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Drug Discovery
  • Cancer Research

Cite this

Rnai screening identifies tak1 as a potential target for the enhanced efficacy of topoisomerase inhibitors. / Martin, S. E.; Wu, Zhaohui; Gehlhaus, K.; Jones, T. L.; Zhang, Y. W.; Guha, R.; Miyamoto, S.; Pommier, Y.; Caplen, N. J.

In: Current Cancer Drug Targets, Vol. 11, No. 8, 01.10.2011, p. 976-986.

Research output: Contribution to journalArticle

Martin, SE, Wu, Z, Gehlhaus, K, Jones, TL, Zhang, YW, Guha, R, Miyamoto, S, Pommier, Y & Caplen, NJ 2011, 'Rnai screening identifies tak1 as a potential target for the enhanced efficacy of topoisomerase inhibitors', Current Cancer Drug Targets, vol. 11, no. 8, pp. 976-986. https://doi.org/10.2174/156800911797264734
Martin, S. E. ; Wu, Zhaohui ; Gehlhaus, K. ; Jones, T. L. ; Zhang, Y. W. ; Guha, R. ; Miyamoto, S. ; Pommier, Y. ; Caplen, N. J. / Rnai screening identifies tak1 as a potential target for the enhanced efficacy of topoisomerase inhibitors. In: Current Cancer Drug Targets. 2011 ; Vol. 11, No. 8. pp. 976-986.
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