Cisplatin (DDP)-based chemotherapy remains one of the standard treatment options for patients with advanced lung adenocarcinoma (LUAD), and cisplatin resistance is the biggest challenge to this therapy. Autophagy is also closely associated with chemoresistance in LUAD. Desperately need to find a way to improve the treatment efficiency of cisplatin-resistant LUAD in clinical practice. Previous studies reported that methylseleninic acid (MSA) has good anti-proliferation and pro-apoptotic activities in tumor cells. However, the effectiveness of MSA on cisplatin-resistant LUAD and its effect on the induction of autophagy is still unclear. In the current study, we found that MSA effectively inhibited the proliferation of LUAD cell lines and triggered mitochondrial pathway-mediated apoptosis. This effect was more pronounced in cisplatin-resistant LUAD cells with high MDR1 expression. In contrast, the mitochondrial damage caused by MSA treatment can be degraded by inducing selective autophagy in LUAD cells, thereby exerting a self-protective effect on tumor cells. Mechanistically, MSA inhibits proliferation, promotes apoptosis, and induces autophagy in LUAD cells by inhibiting of the Akt/mTOR pathway. Combination with autophagy inhibitors reduces the effect of this selective autophagy-induced resistance, and thus enhancing even more the anti-tumor effect of MSA on cisplatin-resistant LUAD cells. Finally, We speculate that MSA in combination with autophagy inhibitors may be a promising new therapeutic strategy for the treatment of cisplatin-resistant LUAD.

Background Esophageal carcinoma (ESCA) is considered to be one of the most common gastrointestinal cancers. Caspase‐8 (CASP8) is a key protein of cross‐talk signaling in a variety of cancers. However, the role of CASP8 expression in the prognosis of patients with ESCA has remained unexplored. Hence, it is needed to explore the clinical significance of CASP8 expression in ESCA. Methods The expression and prognosis of CASP8 were investigated in ESCA using the UALCAN, GEDS, TIMER, and OncoLnc databases. The CASP8 genetic variations in ESCA were assessed using the cBioPortal database. The correlation between CASP8 expression and tumor immune invasion and immune cell surface indicators was examined using the TIMER and TISIDTISIDB datasets. Meanwhile, the abundance of the immunological cells in the tumor and healthy tissues was assessed by the CIBERSORT method. Next, information on the co‐expressed genes of the differentially expressed genes (DEGs) in ESCA‐tumor and ESCA‐healthy tissues was obtained using the cBioPortal, UALCAN, and Coexpedia databases. Subsequently, the PPI network was constructed and the GO and KEGG pathways were analyzed using the SIRING database. Finally, CASP8 mRNA and protein expression in the ESCA tissues and matched adjacent healthy tissues were analyzed using qRT‐PCR, immune‐blotting, and immunohistochemistry. Additionally, the relationship between clinicopathological features and CASP8 expression was assessed. Results ESCA tissues had higher levels of CASP8 mRNA and protein expression compared to healthy tissues. patients with an elevated level of CASP8 expression had poor overall survival (OS). CASP8 expression was significantly correlated with the degree of differentiation (P = 0.004) and lymph node metastasis (P = 0.044). There were diverse patterns of association between immunological cell surface biomarkers and CASP8 expression. Conclusion ESCA showed significant levels of CASP8 expression which may serve as a prognostic biomarker correlated to immune infiltrates in ESCA.

For patients with platinum-resistant lung adenocarcinoma (LUAD), the exploration of new effective drug candidates is urgently needed. Fibroblast growth factor receptors (FGFRs) have been identified as promising targets for LUAD therapy. The purpose of this study was to determine the exact role of the irreversible FGFR1-4 inhibitor FIIN-2 in LUAD and to clarify its underlying molecular mechanisms. Our results demonstrated that FIIN-2 significantly inhibited the proliferation, colony formation, and migration of A549 and A549/DDP cells but induced the mitochondria-mediated apoptosis of these cells. Meanwhile, FIIN-2 increased the autophagy flux of A549 and A549/DDP cells by inhibiting the mammalian target of rapamycin (mTOR) and further activating the class III PI3K complex pathway. More importantly, in vivo and in vitro experiments showed that autophagy inhibitors could enhance the cytotoxicity of FIIN-2 on A549 and A549/DDP cells, confirming that FIIN-2 induced protective autophagy. These findings indicated that FIIN-2 is a potential drug candidate for LUAD treatment, and its use in combination with autophagy inhibitors might be an efficient treatment strategy, especially for patients with cisplatin resistance.

Context Polyphyllin II (PPII) is a steroidal saponin isolated from Rhizoma Paridis . It exhibits significant antitumor activity such as anti-proliferation and pro-apoptosis in lung cancer. Objective To explore whether PPII induce autophagy and the relationship between autophagy and apoptosis in non-small cell lung cancer (NSCLC) cells. Materials and methods The effects of PPII (0, 1, 5, and 10 μM) were elucidated by CCK8 assay, colony formation test, TUNEL staining, MDC method, and mRFP-GFP-LC3 lentivirus transfection in A549 and H1299 cells for 24 h. DMSO-treated cells were selected as control. The protein expression of autophagy (LC3-II, p62), apoptosis (Bcl-2, Bax, caspase-3) and p-mTOR was detected by Western blotting. We explored the relationship between autophagy and apoptosis by autophagy inhibitor CQ (10 μM) and 3-MA (5 mM). Results PPII (0, 1, 5, and 10 μM) inhibited the proliferation and induced apoptosis. The IC 50 values of A549 and H1299 cells were 8.26 ± 0.03 and 2.86 ± 0.83 μM. We found that PPII could induce autophagy. PPII promoted the formation of autophagosome, increased the expression of LC3-II/LC3-I ( p < 0.05), while decreased p62 and p-mTOR ( p < 0.05). Additionally, the co-treatment with autophagy inhibitors promoted the protein expression of c-caspase-3 and rate of Bax/Bcl-2 ( p < 0.05), compared with PPII-only treatment group. Therefore, our results indicated that PPII-induced autophagy may be a mechanism to promote cell survival, although it can also induce apoptosis. Conclusions PPII-induced apoptosis exerts its anticancer activity by inhibiting autophagy, which will hopefully provide a prospective compound for NSCLC treatment.