Investigation of autophagic effects of prion proteins in breast cancer

Cancer cells develop various cellular adaptation mechanisms to survive under harsh environmental conditions and to develop resistance to therapies. In this process, programmed cellular responses such as autophagy and apoptosis play a critical role. These responses help cells maintain homeostasis under stress and enhance their chances of survival. While autophagy facilitates the recycling of cellular components, apoptosis ensures the controlled elimination of damaged or dysfunctional cells. In recent years, the cellular prion protein (PrPc) has attracted attention due to its association with survival, stress response, and multidrug resistance (MDR) mechanisms; however, its precise role in regulating the autophagy-apoptosis balance remains unclear. In this study, the effects of PrPc on the expression of autophagy- and apoptosis-related genes were investigated in triple-negative breast cancer (4T1) and human epidermal growth factor receptor 2-positive (4T1-HER2+) cell lines through the application of the endoplasmic reticulum stressor tunicamycin and PrPc-targeting siRNA. Experimental groups were established in both cell lines as follows: control, IC50 dose and IC50+0.010 µMol/mL tunicamycin doses (0.063 µM/mL and 0.073 µM/mL), PrPc siRNA alone, and siRNA combined with tunicamycin. Following treatment, the expression levels of p62, LC3-II, Bax, Bcl-2, and PrPc genes were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The findings demonstrated that PrPc suppression under stress conditions may differentially influence cellular response mechanisms. In particular, in the 4T1 cell line, co-treatment of PrPc knockdown and IC50 dose of tunicamycin led to significant changes in the expression of p62, LC3-II, Bax, and Bcl-2 genes. In contrast, the HER2-positive cell line exhibited more limited changes under similar treatments, suggesting that PrPc may interact with distinct mechanisms in a cell type-specific manner. In conclusion, PrPc suppression was shown to influence the expression of autophagy- and apoptosis-related genes under stress conditions, potentially modulating the adaptive responses of tumor cells. These results suggest that PrPc may serve as a potential therapeutic target and that PrPc -centered strategies could offer novel approaches for breast cancer treatment.