Apoptosis is programmed cell death which is essential for development and survival of living organisms. It is a sequentially regulated suicidal programme where cells activate certain enzymes which dissolute their own nuclear component and various protein component of nucleus and cytoplasm. Disturbance of this regulatory pathway may lead to various diseases like autoimmune diseases, neurodegenerative diseases and cancers. The potential mechanisms of apoptosis and its role in cancer are discussed. The ability of apoptosis to modulate the life or death of a cell is also recognized for its immense therapeutic potential. Understanding the mechanisms from this review will give us better insight to the pathogenesis of various diseases including cancer and will open new horizons to therapeutic approaches.

Background Phosphorylation is an important regulatory mechanism of protein activity in cells. Studies in various cancers have reported perturbations in kinases resulting in aberrant phosphorylation of oncoproteins and tumor suppressor proteins. Methods In this study, we carried out quantitative phosphoproteomic analysis of gastric cancer tissues and corresponding xenograft samples. Using these data, we employed bioinformatics analysis to identify aberrant signaling pathways. We further performed molecular inhibition and silencing of the upstream regulatory kinase in gastric cancer cell lines and validated its effect on cellular phenotype. Through an ex vivo technology utilizing patient tumor and blood sample, we sought to understand the therapeutic potential of the kinase by recreating the tumor microenvironment. Results Using mass spectrometry-based high-throughput analysis, we identified 1,344 phosphosites and 848 phosphoproteins, including differential phosphorylation of 177 proteins (fold change cut-off ≥ 1.5). Our data showed that a subset of differentially phosphorylated proteins belonged to splicing machinery. Pathway analysis highlighted Cdc2-like kinase (CLK1) as upstream kinase. Inhibition of CLK1 using TG003 and CLK1 siRNA resulted in a decreased cell viability, proliferation, invasion and migration as well as modulation in the phosphorylation of SRSF2. Ex vivo experiments which utilizes patient's own tumor and blood to recreate the tumor microenvironment validated the use of CLK1 as a potential target for gastric cancer treatment. Conclusions Our data indicates that CLK1 plays a crucial role in the regulation of splicing process in gastric cancer and that CLK1 can act as a novel therapeutic target in gastric cancer. Keywords Phosphoserine/threonine • Spliceosome complex • Targeted therapy • Biomarker • PDX in vivo models List of abbreviations CLK Cdc2-like kinase PDX Patient-derived xenografts IHC Immunohistochemistry TMT Tandem Mass Tag bRPLC Basic pH reverse phase chromatography HCD Higher energy collision dissociation IPA Ingenuity pathway analysis FBS Fetal bovine serum Electronic supplementary material The online version of this article (

Our study highlights distinct adverse effects of chronic exposure to DPE/DPE vapor on skin keratinocytes and the potential role of vitamin E in alleviating adverse effects of environmental pollution.

Cigarette smoking has been associated with multiple negative effects on human skin. Long-term physiological effects of cigarette smoke are through chronic and not acute exposure. Molecular alterations due to chronic exposure to cigarette smoke remain unclear. Primary human skin keratinocytes chronically exposed to cigarette smoke condensate (CSC) showed a decreased wound-healing capacity with an increased expression of NRF2 and MMP9. Using quantitative proteomics, we identified 4728 proteins, of which 105 proteins were overexpressed (≥2-fold) and 41 proteins were downregulated (≤2-fold) in primary skin keratinocytes chronically exposed to CSC. We observed an alteration in the expression of several proteins involved in maintenance of epithelial barrier integrity, including keratin 80 (5.3 fold, p value 2.5 × 10), cystatin A (3.6-fold, p value 3.2 × 10), and periplakin (2.4-fold, p value 1.2 × 10). Increased expression of proteins associated with skin hydration, including caspase 14 (2.2-fold, p value 4.7 × 10) and filaggrin (3.6-fold, p value 5.4 × 10), was also observed. In addition, we report differential expression of several proteins, including adipogenesis regulatory factor (2.5-fold, p value 1.3 × 10) and histone H1.0 (2.5-fold, p value 6.3 × 10) that have not been reported earlier. Bioinformatics analyses demonstrated that proteins differentially expressed in response to CSC are largely related to oxidative stress, maintenance of skin integrity, and anti-inflammatory responses. Importantly, treatment with vitamin E, a widely used antioxidant, could partially rescue adverse effects of CSC exposure in primary skin keratinocytes. The utility of antioxidant-based new dermatological formulations in delaying or preventing skin aging and oxidative damages caused by chronic cigarette smoke exposure warrants further clinical investigations and multi-omics research.