Targeting Prion Protein to Overcome Doxorubicin Resistance in SCLC

Multidrug resistance (MDR) remains a major challenge in small cell lung cancer (SCLC), limiting the efficacy of chemotherapeutics like doxorubicin. This study investigates whether silencing cellular prion protein (PrP), a known MDR-associated molecule, can enhance doxorubicin-induced cell death in Adriamycin-resistant H69AR cells. Quantitative RT-PCR and immunocytochemistry were used to assess the expression of PRNP, CD44, BAX, and BECN1 under various treatment conditions, including doxorubicin exposure and PrP knockdown via siRNA. Autophagic activity was evaluated using monodansylcadaverine (MDC) staining. PrP knockdown significantly reduced PRNP expression and modulated CD44 mRNA levels, especially during doxorubicin co-treatment. However, CD44 protein levels remained unchanged, suggesting post-transcriptional regulation. BAX expression increased with doxorubicin and siRNA individually, but not in combination, indicating a PrP-independent mechanism. BECN1 expression and Beclin-1 protein levels were significantly elevated in all treatment groups, especially in siRNA/doxorubicin combination. MDC staining confirmed increased autophagic vacuole formation in this group, indicating activation of Beclin-1-mediated autophagy. In conclusion, PrP knockdown may sensitize resistant SCLC cells to doxorubicin and promote autophagy. These findings support PrP silencing as a promising strategy to reverse chemoresistance in SCLC.