In addition, S100A8 was found to be crucial for regulating drug resistance and promoting autophagy in BCL cells. resistance and promoting autophagy in BCL cells. Interference of S100A8 significantly Rabbit Polyclonal to SCNN1D MA242 downregulated Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 located in the mitochondria and endoplasmic reticulum to further inhibit autophagy. In addition, S100A8 interference markedly inhibited the formation of the BECN1-PI3KC3 complex and promoted B-cell lymphoma 2 expression, which collectively inhibited autophagy. but cellular chemoresistance experiments in vitro; therefore, the broad-spectrum chemotherapy drugs ADR and VCR were selected in the present study instead of rituximab. Autophagy, also referred to as type II programmed cell death, is an evolutionarily conserved and strictly controlled metabolic process. Autophagy plays an important role in homeostasis and cell survival. Cancer cells have multiple responses to chemotherapy, from activating survival pathways to triggering cell death (41,42). Chemotherapy drugs can significantly increase the autophagic activity of BCL cells (43). Multiple studies have demonstrated that inhibition of autophagy enhances chemotherapy-induced BCL cell death (44C46). However, the specific molecular regulatory effects of S100A8 on autophagy and chemoresistance in BCL cells remain unclear. The present study indicated that the drug resistance of BCL cells was positively correlated with autophagic activity, and S100A8 was closely associated with the drug resistance of BCL cells by activating autophagy. Prior to this study, S100A8 has been MA242 reported to promote autophagy in cancer cells through the cross-talk between mitochondria and lysosomes via reactive oxygen species (32), or through the activation of the autophagy initiation complex BECN1-PI3KC3 (30). In the present study, it was confirmed that S100A8 reduced the sensitivity of BCL cells to chemotherapy by maintaining BCL cell autophagy, thereby increasing the resistance of BCL cells to chemotherapy. The role of the S100A8 protein in pro-autophagic activities is mediated through the promotion of BECN1-PI3KC3 and BECN1-BCL2 complex formation (31). This study revealed that S100A8 stimulated BECN1-PI3KC3 complex formation as an early autophagic signalling event that significantly promoted autophagy. In addition, the dissociation of BCL2 from BECN1 was found to be an important mechanism involved MA242 in S100A8-activated autophagy. LC3 is initially processed into its cytoplasmic form, LC3-I, then coupled with lipid phosphatidylethanolamine, generating its final LC3-II form (47). BNIP3 is a cell death-inducing factor of the Bcl-2 family of proteins, more precisely a member of the BH3-only subfamily. Proteins such as S100A8 in the BH3-only subfamily bind through a common BH3 domain, rather than the BH1 and BH2 domains as the other Bcl-2 family members. The binding of BNIP3 to LC3 is crucial for autophagosome formation (47,48). The present study demonstrated that S100A8 accelerated BNIP3 expression in ER and mitochondria, resulting in the promotion of autophagy. In conclusion, the molecular mechanisms of S100A8-triggered autophagy and drug resistance of BCL cells was investigated MA242 in the present study. The involvement of the S1008-BNIP3/BECN1-PI3KC3 complex-autophagy-chemoresistance axis in the autophagic regulation of drug resistance in BCL cells was also confirmed. These findings may help overcome drug resistance in the treatment of BCLs. Acknowledgements Not applicable. Funding The present study was funded by the Key Research Project from Science & Technology Department MA242 of Sichuan Province (grant no. 2019YFS0301); The Doctor Research Foundation of The Affiliated Hospital of Southwest Medical University (grant nos. 19032 and 19079); The Key Research Project from Health and Family Planning Commission of Sichuan Province (grant no. 18ZD014); The Applied Basic Research Project of Luzhou Science and Technology Bureau (grant no. 2019LZXNYDJ54); and the National Natural Science Foundation of China (grant no. 81450030). Availability of data and materials All data generated or analyzed during this study are included in this published article. Authors’ contributions LZ performed the experiments and data analysis and wrote the manuscript. SZ, TZ, KY and XL participated in conducting this study. JT designed and oversaw this study, and contributed to the revision of the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate All institutional and national guidelines for the use of laboratory materials were followed. Patient consent for publication Not applicable. Competing interests All the authors declare that they have no competing interests..
In addition, S100A8 was found to be crucial for regulating drug resistance and promoting autophagy in BCL cells