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Metformin Induces PARP1-mediated Cell Death in NPC/HK1 Human Nasopharyngeal Carcinoma Cells
Chih-Chun Wang1,2,3, Yaw-Chang Huang1,2, Chief-Chung Wang1,2
1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C.
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.
Insights
Metformin inhibits nasopharyngeal carcinoma cell viability through PARP1-mediated cell death, not apoptosis or autophagy. This highlights the PARP1/PAR/AIF pathway as a potential therapeutic target for NPC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Pathways
Background:
- Nasopharyngeal carcinoma (NPC) frequently metastasizes, leading to treatment failure and poor prognosis.
- Metformin shows anticancer potential in NPC, but its precise mechanism for inhibiting tumor cell viability is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which metformin reduces the viability of NPC cells.
- To elucidate the specific cell death pathways involved in metformin's anti-NPC effects.
Main Methods:
- NPC/HK1 cells were treated with metformin.
- Cell viability was assessed using MTT assays.
- Apoptosis, autophagy, and parthanatos markers (PAR accumulation, MMP, PARP1/AIF localization) were analyzed.
- PARP inhibitors (3-ABA, DPQ) were used for functional validation.
Main Results:
- Metformin dose-dependently decreased NPC/HK1 cell viability.
- Metformin did not significantly induce apoptosis or autophagy.
- Metformin activated parthanatos, evidenced by increased PAR accumulation, disrupted mitochondrial membrane potential, and nuclear translocation of PARP1 and AIF.
- PARP inhibitors partially reversed metformin's effect on cell viability.
Conclusions:
- Metformin suppresses NPC cell viability primarily through PARP1-mediated parthanatos.
- The PARP1/PAR/AIF signaling axis represents a promising therapeutic target and potential biomarker for NPC.
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