Background Autophagy is an intracellular process through which intracellular components are recycled in response to nutrient or growth factor deficiency to maintain homeostasis. We identified the peptide autophagy-related cancer-suppressing peptide (ARCSP), a potential antitumor peptide that disrupts intracellular homeostasis by blocking autophagic flux and causes cytotoxic death. Methods The proliferative ability of ARCSP-treated cervical cancer cells was examined by the CCK8, EdU, and colony formation assays. The TUNEL assay was used to detect apoptosis. Mitochondrial function was evaluated based on the mitochondrial membrane potential. Autophagic flux was detected by immunofluorescence and confocal microscopy. The autophagy-related proteins AMPK, Raptor, mTOR, p62, LC3B, atg7, Rab7, LAMP1, LAMP2, and cathepsin D were detected by Immunoblotting. The antitumor effect of ARCSP was explored in vivo by establishing a transplant tumor model in nude mice. Results The results demonstrated that ARCSP induced cell death and inhibited proliferation. ARCSP induced AMPK/mTOR activation, resulting in the accumulation of the proteins LC3B, p62 and Atg7. ARCSP also blocked autophagosome-lysosome fusion by inhibiting endosomal maturation and increasing the lysosomal pH. The accumulation of nonfused autophagosomes exacerbated cytotoxic death, whereas knocking down Atg7 reversed the cytotoxic death induced by ARCSP. ARCSP-treated cells exhibited increased cytotoxic death after cotreatment with an autophagy inhibitor (Chloroquine CQ). Furthermore, the tumors of ARCSP-treated nude mice were significantly smaller than those of untreated mice. Conclusions Our findings demonstrate that ARCSP, a novel lethal nonfused autophagosome inducer, might cause mitochondrial dysfunction and autophagy-related cytotoxic death and is thus a prospective agent for cancer therapy.

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We used blood serum samples collected from 31 lung cancer (LC) patients and 29 healthy volunteers in this study. Levels of serum metabolites were qualitative quantified with gas chromatography-mass spectrometry (GC-MS), and the data were analyzed by partial least-squares discrimination analysis (PLS-DA). Based on the Kyoto Encyclopedia of Genes and Genomes database, we performed pathwaybased analysis utilizing metabolites presented at differential abundance between the LC serum samples and the normal healthy serum samples for systematical investigation on the metabolic alterations associated with LC pathogenesis. Finally, we analyzed the significantly enriched pathways as well as their relevant differentially expressed messenger RNAs, and drawn a correlation network plot to identify the serum metabolic biomarkers and the significantly altered metabolic pathways for LC. GC-MS analysis showed that 23 of the 169 metabolites identified were significantly different. PLS-DA model revealed that 13 of these metabolites were with variable importance > 1, and particularly five were with area under curve > 0.9. Pathway-based analysis demonstrated that five of eight enriched metabolic pathways were statistically significant with false discovery rate < 0.05. Lastly, the correlation networks between these pathways and their related genes suggested that 29 genes had correlation degree > 10, which were mainly engaged in the purine metabolism. In conclusion, we identified indole-3-lactate, erythritol, adenosine-5-phosphate, paracetamol and threitol as serum metabolic biomarkers for LC through metabolomics analysis. Besides, we identified the purine metabolism as the significantly altered metabolic pathway in LC with the help of transcriptomics analysis. K E Y W O R D S lung cancer, metabolomics, serum, transcriptomics | INTRODUCTIONTo date, lung cancer (LC) has become one of the most common cancer all over the world, with 1.8 million new cases of LC and 1.6 million deaths in 2012. 1 In spite of great efforts in early diagnosis of LC, it still remained the leading cause of cancer-related deaths in men and the second leading cause in women second to breast cancer. 1 Currently, common diagnostic approaches included chest radiograph, computed tomography scan, fiberoptic bronchoscopy, magnetic resonance imaging and positron emission tomography. 2 Unfortunately, these techniques hardly provide useful

Our results, together with those of others pointing in the same direction, suggest that genotyping the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.