HMGB1 modulates the balance between senescence and apoptosis in response to genotoxic stress

• DOI: 10.1096/fj.201900288r
• Publication Date: 2019-07-09T02:37:15Z
• Authors: Je-Jung Lee; In Ho Park; Woo Joong Rhee; Hee Sue Kim; Jeon-Soo Shin
• Keywords: Senescence; HMGB1; Cellular stress response

High mobility group box-1 (HMGB1) is involved in various diseases and associated with the resistance of many types human cancers to chemotherapy; however, its role cancer metastasis remains unexplored. This study examined HMGB1 status both highly poorly metastatic cells response genotoxic stress. The weakly mouse melanoma cell lines (B16 vs. B16-F10), (SK-MEL-28 SK-MEL-24), colon (DLD-1 LS174T), wild-type (WT) knockout (KO) embryonic fibroblasts (MEFs) were treated doxorubicin (Dox) camptothecin (CPT), then cellular morphology, senescence-associated β-galactosidase staining, lactate dehydrogenase release, caspase-3 activation used assess fate. To investigate p21 expression, expressions by Western blotting, HMGB1-mediated promoter luciferase assay was performed after small interfering RNA or overexpression prior Dox treatment. Although B16-F10 preferred senescence, persistent B16 entered apoptosis, decreasing levels via cleavage under Similarly, more SK-MEL-24 LS174T underwent whereas fewer SK-MEL-28 DLD-1 exhibited apoptosis stimulation. In senescent B16-F10, SK-MEL-24, Dox, increased expression. Furthermore, depletion caused a senescence-apoptosis shift down-regulation cells, switched from senescence concomitantly expression same effects observed pairs CPT, another stressor. Indeed, although WT MEF accompanied increase, KO decrease our model system, we demonstrated that preferentially enter predominates stress, which depends on presence absence HMGB1, suggesting HMGB1-p21 axis required for stress–induced senescence. These findings suggest modulation different could be strategy selectively enforcing tumor suppression.—Lee, J.-J., Park, I. H., Rhee, W. J., Kim, H. S., Shin, J.-S. modulates balance between FASEB J. 33, 10942–10953 (2019). www.fasebj.org