Abstract
Autophagy is a conserved catabolic process essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy plays a dual role, acting as both a tumor suppressor and promoter depending on the stage and context. Unc-51-like kinase 1 (ULK1), a key initiator of autophagy, is tightly regulated by USP20, a de-ubiquitinase that stabilizes ULK1 by preventing its lysosomal degradation. However, their roles in cancer progression and treatment response remain poorly understood. The present study investigated the baseline expression of ULK1 and USP20 across several cancer cell lines and evaluates the effects of their silencing on chemosensitivity. The findings of the present study showed that ULK1 was highly expressed in MCF-7 breast cancer cells and minimally in U87 glioblastoma cells. USP20 showed high expression in MCF-7, MDA-MB-231 and HepG2, and low expression in others. Combined silencing of ULK1 and USP20 with chemotherapy altered drug sensitivity across cancer types. ULK1 knockdown increased drug sensitivity and induced cell death in HepG2, MDA-MB-231 and PanC1 cell lines, but conferred chemoresistance in MCF-7, A549 and U87 cancer cells. Similarly, USP20 silencing sensitized MCF-7, HepG2 and PanC1 cells to chemotherapy, while enhancing survival in U87 cells. These results suggest that ULK1 and USP20 have cancer-type-specific roles in modulating autophagy and chemotherapy response. Targeting these proteins may provide novel therapeutic strategies to overcome chemoresistance and promote apoptosis in cancer treatment.