Cathepsin D and eukaryotic translation elongation factor 1 as promising markers of cellular senescence.
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 1beta2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 1alpha1 (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 microg 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.
Byun
Hae-Ok
HO
Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Han
Na-Kyung
NK
Lee
Hae-June
HJ
Kim
Ki-Bum
KB
Ko
Young-Gyu
YG
Yoon
Gyesoon
G
Lee
Yun-Sil
YS
Hong
Seok-Il
SI
Lee
Jae-Seon
JS
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011829:Radiation Dosage; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015415:Biomarkers; D020648:Peptide Elongation Factor 1; D034741:RNA, Small Interfering; C533922:CTSD protein, human; D002402:Cathepsin D