CDGSH iron sulfur domain 2 (CISD2) is localized in the outer mitochondrial membrane and mediates mitochondrial integrity and lifespan in mammals, but its role in cancer is unknown. In the current study, we reported that CISD2 mRNA and protein expression levels were significantly upregulated in gastric cancer cells compared to normal gastric epithelial cells (P < 0.001). Immunohistochemical analysis of 261 paraffin-embedded archived gastric cancer tissues showed that high CISD2 expression was significantly associated with clinical stage, TNM classifications, venous invasion and lymphatic invasion. Univariate and multivariate analysis indicated that high CISD2 expression was an independent prognostic factor for poorer overall survival in the entire cohort. Overexpressing CISD2 promoted, while silencing CISD2 inhibited, the proliferation of gastric cancer cells. Furthermore, we found that silencing endogenous CISD2 also significantly inhibited the proliferation and tumorigenicity of MGC-803 and SGC-7901 cells not only in vitro but also in vivo in NOD/SCID mice (P < 0.05). Furthermore, we found that CISD2 affected cell proliferation and tumorigenicity of gastric cancer cells through mediating the G1-to-S phase transition. Moreover, we demonstrated that the pro-proliferative effect of CISD2 on gastric cancer cells was associated with downregulation of cyclin-dependent kinase inhibitor p21Cip1 and p27Kip1, and activation of AKT signaling. The findings of this study indicate that CISD2 may promote proliferation and tumorigenicity, potentially representing a novel prognostic marker for overall survival in gastric cancer.

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We have previously reported that temporin-1CEa, a cationic antimicrobial peptide, exerts preferential cytotoxicity toward cancer cells. However, the exact molecular mechanism for this cancer-selectivity is still largely unknown. Here, we found that the negatively charged phosphatidylserine (PS) expressed on cancer cell surface serves as a target for temporin-1CEa. Our results indicate that human A375 melanoma cells express 50-fold more PS than non-cancerous HaCaT cells. The expression of cell surface PS in various cancer cell lines closely correlated with their ability to be recognized, bound and killed by temporin-1CEa. Additionally, the cytotoxicity of temporin-1CEa against A375 cells can be ameliorated by annexin V, which binds to cell surface PS with high affinity. Moreover, the data of isothermal titration calorimetry assay further confirmed a direct binding of temporin-1CEa to PS, at a ratio of 1:5 (temporin-1CEa:PS). Interestingly, the circular dichroism spectra analysis using artificial biomembrane revealed that PS not only provides electrostatic attractive sites for temporin-1CEa but also confers the membrane-bound temporin-1CEa to form α-helical structure, therefore, enhances the affinity and membrane disrupting ability of temporin-1CEa. In summary, these findings suggested that the melanoma cells expressed PS may serve as a promising target for temporin-1CEa or other cationic anticancer peptides.

Ouabain is a cardiotonic steroid with a history of medical uses. It acts as a ligand to the ubiquitous ion pump Na+,K+‐ATPase which it inhibits at high concentrations. At lower concentrations it triggers calcium oscillations and activation of MAP kinases, stimulates cell proliferation as well as adhesion and acts anti‐apoptotic. In light of this, it has been proposed that the pump may have a dual function as a signaling transducer. To investigate this, we have analyzed the phosphoproteome of COS‐7 kidney cells after treatment with sub‐saturating levels (100 nM) of ouabain, which were high enough to induce Ca2+ oscillations but below those needed to modulate the ion pumping function of Na+,K+‐ATPase. Gene ontology analysis was performed to find distinct cellular processes regulated by ouabain after 10 and 20 min of treatment in the phopshoproteomic analysis. The analysis revealed 2580 ouabain‐regulated phosphorylation sites, many of which were associated with cell adhesion and proliferation. Two of the regulated phospho‐proteins were the inositol triphosphoate receptor (InsP3) and stromal interaction molecule (STIM), both of which are essential for ouabain‐induced calcium oscillations. We used siRNA and Western blotting for target confirmation. One confirmed target, calcium/calmodulin‐dependent protein kinase II gamma (CAMK2γ), were shown to be involved in the anti‐apoptotic effect of ouabain; siRNA silencing of CaMK2γ in primary renal cells eliminates the protective effect of ouabain against apoptosis induced by either serum starvation or glucose. In conclusion, our findings support a role for Na+,K+‐ATPase as a signal transducer that serves to protect cell and tissue integrity. Support or Funding Information This study was supported by the Swedish Research Council and Erling‐Persson Family Foundation. D.S. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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