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

Abstract

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 1B2 (eEF1B2), as confirmed by Western blot. The other elongation factor, eukaryotic translation elongation factor 1A1 (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 Mg 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]

Heparan sulfation is essential for the prevention of cellular senescence

“…However, cancer cells can be readily induced to undergo premature senescence by the hyperactivation of oncogenes, the loss of tumor suppressors, and a variety of stresses in vitro and in vivo. [44][45][46][47] To our knowledge, no study has elucidated the importance of sulfation status in the regulation of cellular senescence, although tremendous attention has been paid to the role of sulfated PGs in a variety of other biological processes. Here, we demonstrate that the undersulfation of HSPGs, in particular desulfation at the 2-O position of iduronate in HS, prematurely induces cellular senescence through augmented FGFR signaling pathway.…”

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

“…18,19 Indeed, if cellular senescence pathways remain intact, senescence induction could compensate for the inactivation of the apoptotic pathway and could be triggered with low doses of chemotherapeutic drugs or IR. 20 Therefore, it is possible that improved tumor treatments could be developed by understanding the mechanism of premature senescence. 9 Gliomas are the most common malignant brain tumor in adults and are among the most lethal of all cancers.…”

“…We also previously reported that IR induces premature senescence in breast, colon, and lung carcinoma, and in tumor tissue of xenografted mice. 20,39 Therefore, understanding premature senescence mechanisms could provide helpful information for improving the efficacy of RT.…”

EEF1A1 (eukaryotic translation elongation factor 1 alpha 1)

“…Down-regulation of eEF1A1 seems to be specific to senescence. Changes in eEF1A expression levels has been proposed also as promising marker for the detection of cellular cancer senescence induced by a variety of treatments, such as ionizing radiation (Byun et al, 2009). 4) eEF1A1 and cell signalling modulation.…”