Radiation and chemotherapy represent standard‐of‐care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio‐ and chemotherapy, we exposed human cancer cell lines (HeLa, MCF‐7 and DU 145) to clinically relevant doses of 5‐azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low‐adherent stem‐like cells. Stress‐mobilized low‐adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon‐gamma but not interferon‐beta resulted in the development of a heterogeneous, low‐adherent fraction comprising not only apoptotic/necrotic cells but also live cells exhibiting active Notch signalling and expressing stem‐cell markers. Chemical inhibition of mitogen‐activated protein kinase/ERK kinase ( MEK ) or si RNA ‐mediated knockdown of extracellular signal‐regulated kinase 1/2 (Erk1/2) and interferon responsible factor 1 ( IRF 1) prevented mobilization of the surviving low‐adherent population, indicating that interferon‐gamma‐mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF 1. Notably, a skin‐specific protein suprabasin ( SBSN ), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low‐adherent cancer cells induced by 5‐azacytidine or irradiation. SBSN expression required the activity of the MEK /Erk pathway, and si RNA ‐mediated knockdown of SBSN suppressed the low‐adherent fraction in irradiated, interferon‐gamma‐ and 5‐azacytidine‐treated cells, respectively, implicating SBSN in genotoxic stress‐induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.
Cellular senescence is a complex stress response defined as an essentially irreversible cell cycle arrest mediated by the inhibition of cell cycle-specific cyclin dependent kinases. The imbalance in redox homeostasis and oxidative stress have been repeatedly observed as one of the hallmarks of the senescent phenotype. However, a large-scale study investigating protein oxidation and redox signaling in senescent cells in vitro has been lacking. Here we applied a proteome-wide analysis using SILAC-iodoTMT workflow to quantitatively estimate the level of protein sulfhydryl oxidation and proteome level changes in ionizing radiation-induced senescence (IRIS) in hTERT-RPE-1 cells. We observed that senescent cells mobilized the antioxidant system to buffer the increased oxidation stress. Among the antioxidant proteins with increased relative abundance in IRIS, a unique 1-Cys peroxiredoxin family member, peroxiredoxin 6 (PRDX6), was identified as an important contributor to protection against oxidative stress. PRDX6 silencing increased ROS production in senescent cells, decreased their resistance to oxidative stress-induced cell death, and impaired their viability. Subsequent SILAC-iodoTMT and secretome analysis after PRDX6 silencing showed the downregulation of PRDX6 in IRIS affected protein secretory pathways, decreased expression of extracellular matrix proteins, and led to unexpected attenuation of senescence-associated secretory phenotype (SASP). The latter was exemplified by decreased secretion of pro-inflammatory cytokine IL-6 which was also confirmed after treatment with an inhibitor of PRDX6 iPLA2 activity, MJ33. In conclusion, by combining different methodological approaches we discovered a novel role of PRDX6 in senescent cell viability and SASP development. Our results suggest PRDX6 could have a potential as a drug target for senolytic or senomodulatory therapy.
Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology.
Aberrantly expressed suprabasin ( SBSN ) is a novel biomarker in myelodysplastic syndrome (MDS) patients. The highest levels of SBSN, secreted from myeloid subpopulations, including myeloid‐derived suppressor cells, are detectable within bone marrow (BM) and peripheral blood plasma of poor prognosis MDS subgroup. SBSN negatively correlated with BM T cells and CCL2 levels indicating immunosuppressive milieu in BM of MDS patients.
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