Metformin Induces PARP1-mediated Cell Death in NPC/HK1 Human Nasopharyngeal Carcinoma Cells

Background/Aim: Nasopharyngeal carcinoma (NPC) in endemic regions remains prone to treatment failure and poor prognosis due to distant metastasis, underscoring the need for novel therapeutic strategies. Metformin exhibits anticancer activity in NPC; however, the mechanism underlying its single-agent inhibition of tumor cell viability remains incompletely defined. This study investigated the molecular basis of metformin-induced viability inhibition in NPC cells.

Materials and Methods: NPC/HK1 cells were used in this study. Cell viability was quantified using the MTT assay. Apoptosis- and autophagy-associated markers were assessed by immunoblotting. Parthanatos-related events were evaluated by measuring poly(ADP-ribose) (PAR) accumulation, mitochondrial membrane potential (MMP) disruption using JC-1 staining, and the subcellular localization of poly(ADP-ribose) polymerase 1 (PARP1) and apoptosis-inducing factor (AIF) by nuclear/cytoplasmic fractionation. Functional validation was performed using the PARP inhibitors 3-aminobenzamide (3-ABA) and DPQ.

Results: Metformin reduced NPC/HK1 cell viability in a dose- and time-dependent manner (IC₅₀=2.5 mg/ml). Metformin did not significantly induce apoptosis or autophagy, as canonical markers were not increased. In contrast, metformin increased PAR accumulation, disrupted MMP, elevated nuclear PARP1 levels, and promoted AIF translocation, consistent with parthanatos activation. Importantly, 3-ABA and DPQ partially rescued metformin-induced loss of viability in NPC/HK1 cells.

Conclusion: Metformin suppresses NPC/HK1 cell viability predominantly via PARP1-mediated cell death rather than apoptosis or autophagy, highlighting the PARP1/PAR/AIF axis as a mechanistically informed therapeutic target and potential response biomarker in NPC.