Committee Members

Abstract:

Bcl-2 is an anti-apoptotic protein that promotes cell survival and resistance to cell death. Predictably, Bcl-2 as well as other anti-apoptotic Bcl-2 family members have been found to be overexpressed in a variety of human cancers. Approaches to overcome apoptotic resistance afforded by Bcl-2 in cells include anti-sense oligonucleotides, drugs that inhibit Bcl-2 function, and BH3 mimics have not been universally effective; thus, the need to understand the underlying mechanism of this resistance is vital. Glucocorticoids are stress hormones that act through their cognate receptors to control the transcription of numerous target genes, and in turn regulate a diverse array of biological processes. Synthetic glucocorticoids, such as dexamethasone, are prescribed in many chemotherapy protocols for neoplasms of lymphoid origin based on their ability to inhibit lymphocyte proliferation and promote apoptosis. However, lymphoid cells expressing Bcl-2 are resistant to glucocorticoid-induced cell death. We observed both pro- and anti-apoptotic characteristics in lymphoid cells expressing Bcl-2 following glucocorticoid treatment. We hypothesized that exploiting one or more of the established glucocorticoid-associated apoptotic characteristics may sensitize S49 Bcl-2 cells to undergo cell death. Interestingly, these cells exhibited a profound change in their intracellular ionic composition, but a limited apoptotic ion flux and the absence of cell death. We show that mimicking the loss of intracellular potassium using a low dose of a microbial toxin that acts as a potassium ionophore, in combination with dexamethasone, overcame the resistance afforded by Bcl-2 and killed the cells. Extending our study using other potassium ionophores revealed that direct depolarization of the mitochondria membrane potential coupled with prior treatment with glucocorticoids is the key mechanism for activating the cell death program and bypassing the resistance afforded by Bcl-2 in lymphoid cells. Finally, we show that the duration of dexamethasone pre-treatment is critical for regulating distinct genes and signaling pathways that sensitize the cells to die.

Meng Yu is an Associate Professor (Principal Investigator) and Master Supervisor of Southern Medical University, Guangzhou, China. Now she is working in École Normale Supérieure, Paris, France as a visiting scholar since Sep 2022. In recent years, Meng YU’s work has focused on improving the new antitumor nanomedicine strategies to overcome therapeutic resistance by regulating the disease-promoting microenvironment. She has over 40 publications, including ACS Nano, Advanced Science, Nano Letters, Small Methods, Bioactive Materials, Biomaterials, J Control Release and so on. The total SCI citations were over 1400 in the last five years with an H-index of 24. Have 3 authorized Chinese Patents. She is the youth board member of the Asian Journal of Pharmaceutical Sciences and Chinese Chemical Letters, two well-recognized international journals.