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Cathepsin D and Eukaryotic Translation Elongation Factor 1 as Promising Markers of Cellular Senescence

Divisions of ¹ Radiation Cancer Research and ² Radiation Effects, and ³ Department of Laboratory Medicine and Clinical Pathology, Korea Institute of Radiological and Medical Sciences; ⁴ Graduate School of Life Sciences and Biotechnology, Korea University, Seoul, Korea and ⁵ Department of Biochemistry, School of Medicine, and Department of Molecular Science and Technology, Graduate School, Ajou University, Suwon, Korea

Requests for reprints: Jae-Seon Lee, Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea. Phone: 82-2-970-1388; Fax: 82-2-970-1388; E-mail: jaeslee{at}kcch.re.kr.

Key Words: Marker • Senescence • Cathepsin D • eEF1 • Cancer therapy

Induction of premature senescence may be a promising strategy for cancer treatment. However, biomarkers for senescent cancer cells are lacking. To identify such biomarkers, we performed comparative proteomic analysis of MCF7 human breast cancer cells undergoing cellular senescence in response to ionizing radiation (IR). IR-induced senescence was associated with up-regulation of cathepsin D (CD) and down-regulation of eukaryotic translation elongation factor 1β2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 11 (eEF1A1), was also down-regulated. IR-induced senescence was associated with similar changes of CD and eEF1 (eEF1A1 and eEF1B2) levels in the HCT116 colon cancer cell line and the H460 lung cancer cell line. Up-regulation of CD and down-regulation of eEF1 seemed to be specific to senescence, as they were observed during cellular senescence induced by hydrogen peroxide or anticancer drugs (camptothecin, etoposide, or 50 ng doxorubicin) but not during apoptosis induced by Taxol or 10 µg doxorubicin or autophagy induced by tamoxifen. The same alterations in CD and eEF1A1 levels were observed during replicative senescence and Ras oncogene-induced senescence. Transient cell cycle arrest did not alter levels of eEF1 or CD. Chemical inhibition of CD (pepstatin A) and small interfering RNA–mediated knockdown of CD and eEF1 revealed that these factors participate in cell proliferation. Finally, the senescence-associated alteration in CD and eEF1 levels observed in cell lines was also observed in IR-exposed xenografted tumors. These findings show that CD and eEF1 are promising markers for the detection of cellular senescence induced by a variety of treatments. [Cancer Res 2009;69(11):4638–47]