Downregulation of CD44 reduces doxorubicin resistance of CD44+CD24- breast cancer cells

Pham Van Phuc, Phan Lu Chinh Nhan, Truong Hai Nhung, Nguyen Thanh Tam, Nguyen Minh Hoang, Vuong Gia Tue, Duong Thanh Thuy, Phan Kim NgocLaboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh, VietnamBackground: Cells within breast cancer stem cell populations have been confirmed to have a CD44+CD24- phenotype. Strong expression of CD44 plays a critical role in numerous types of human cancers. CD44 is involved in cell differentiation, adhesion, and metastasis of cancer cells.Methods: In this study, we reduced CD44 expression in CD44+CD24- breast cancer stem cells and investigated their sensitivity to an antitumor drug. The CD44+CD24- breast cancer stem cells were isolated from breast tumors; CD44 expression was downregulated with siRNAs followed by treatment with different concentrations of the antitumor drug.Results: The proliferation of CD44 downregulated CD44+CD24- breast cancer stem cells was decreased after drug treatment. We noticed treated cells were more sensitive to doxorubicin, even at low doses, compared with the control groups.Conclusions: It would appear that expression of CD44 is integral among the CD44+CD24- cell population. Reducing the expression level of CD44, combined with doxorubicin treatment, yields promising results for eradicating breast cancer stem cells in vitro. This study opens a new direction in treating breast cancer through gene therapy in conjunction with chemotherapy.Keywords: antitumor drugs, breast cancer stem cells, CD44, CD44+CD24- cells, doxorubici

Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease

Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. For Alzheimer’s, Parkinson’s, Huntington’s diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer