Bcl-x_L/Bak interaction and regulation by miRNA let-7b in the intrinsic apoptotic pathway of stored platelets

Abstract

Bcl-2 family proteins play key roles in the intrinsic apoptosis pathway in platelets, with both pro- and antiapoptotic protein expressions regulating survival during ex vivo storage. We detected a significant decrease in antiapoptotic Bcl-x and increase in proapoptotic Bak expression on the third day of storage and as a result the ratio of Bak:Bcl-x also decreased. Moreover, we identified an interaction between Bcl-x and Bak. These shifts corresponded with activation of the apoptotic pathway, suggesting these proteins might play an important role in platelet survival. We then performed bioinformatic analysis to gain insight into protein expression regulation during storage. This identified a potential binding site of the microRNA (miRNA) let-7b in the 3'-UTR of the Bcl-x gene, which we confirmed by a dual-luciferase reporter assay. We also determined that let-7b was upregulated during platelet storage, and let-7b transfection influenced Bcl-x and Bak protein, but not mRNA, expression. Together, these data suggest that only posttranscriptional mechanisms are available for regulating gene expression in anucleate platelets.

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

“…However, the interaction between BCL-xL and let-7a-5p was seldom reported in lung cancer. Limited evidence suggests that let-7b inhibited the expression of BCL-xL in platelets 42 and bioengineered let-7c inhibited orthotopic hepatocellular carcinoma via suppressing the expression of BCL-xL 43 . Collectively, we may conclude that the expression of BCL-xL is negatively correlated with let-7a-5p and dysregulation of BCL-xL/let-7a-5p alters the survival of lung cancer, which is potentially associated with the pathogenesis of lung cancer.…”

Expression and regulation of ccBAX by miR‐124 in the caudal fin cell of C. auratus gibelio upon cyprinid herpesvirus 2 infection

“…Studies on miRNAs involved in BAX‐mediated apoptosis were very limited in fish compared to mammals (Fei, Feng, et al., 2020). Previous studies proved that miR‐124 down‐regulated the expression of BAX protein to suppress apoptosis in rats following spinal cord injury, and miRNA let‐7b suppressed apoptosis in platelets via down‐regulating BAX expression (Xu et al., 2019; Yan et al., 2019). Furthermore, miRNA‐124 was proved to down‐regulate expression of ccBAX of silver crucian carps in this study.…”

“…Previous studies proved that miR-124 down-regulated the expression of BAX protein to suppress apoptosis in rats following spinal cord injury, and miRNA let-7b suppressed apoptosis in platelets via down-regulating BAX expression (Xu et al, 2019;Yan et al, 2019).…”

BH3 profiling discriminates the anti‑apoptotic status of 5‑fluorouracil‑resistant colon cancer cells

“…These results prompted us to consider trying a combination of 5-FU and BCLXL inhibitor prior to the acquisition of 5-FU resistance. However, as BCLXL plays a pivotal role in determining platelet life span (23), the combination of BCLXL inhibitor with a cytotoxic drug may cause severe thrombocytopenia. Indeed, clinical studies targeting BCLXL in glioblastoma multiforme (NCT00540722; ) and small cell lung cancer (NCT03080311; ) are ongoing; monotherapy has been conducted in these studies.…”