MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos
Chunshuang Li1, Yaoyao Xue1, Jiaxin Wu1
1The Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, Jilin 130024, China; School of Life Sciences, Northeast Normal University, Changchun, Jilin 130024, China.
Abstract:
Cervical cancer cells possess high levels of reactive oxygen species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical cancer chemotherapy.
Insights
Increasing oxidative stress via reactive oxygen species (ROS) can induce cervical cancer cell death. Combining ROS agents with MTH1 inhibitors enhances DNA damage, offering a safer chemotherapy strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cervical cancer cells exhibit high reactive oxygen species (ROS) levels, making oxidative stress a potential chemotherapeutic target.
- Existing strategies face challenges with mechanism elucidation, efficacy, and toxicity.
- 8-oxo-7,8-dihydroguanine (8-oxoG) is a key DNA lesion repaired by 8-oxoguanine glycosylase 1 (OGG1).
- MutT homolog 1 (MTH1) prevents 8-oxoG incorporation into DNA by hydrolyzing 8-oxo-dGTP.
Purpose of the Study:
- To investigate the cell death mechanisms in cervical cancer induced by ROS-inducing agents.
- To explore the synergistic effects of MTH1 inhibitors with ROS-inducing agents in cervical cancer treatment.
- To evaluate the therapeutic potential of targeting DNA repair pathways in cervical cancer.
Main Methods:
- Induction of oxidative stress in cervical cancer cells using ROS-inducing agents.
- Assessment of cell death pathways, focusing on parthanatos and DNA damage.
- Inhibition of MTH1 and evaluation of its synergy with ROS agents.
- In vivo studies using tumor xenografts to assess therapeutic efficacy.
- Genetic manipulation (OGG1 knockout) to confirm the role of OGG1 in observed effects.
Main Results:
- ROS-inducing agents triggered parthanatos in cervical cancer cells, primarily via DNA strand breaks from OGG1-mediated 8-oxoG excision.
- MTH1 inhibition enhanced 8-oxoG accumulation in DNA, synergizing with ROS agents.
- The combination therapy suppressed tumor xenograft growth in vivo.
- Tumor growth inhibition was significantly reduced in OGG1-deficient models, confirming OGG1's crucial role.
Conclusions:
- The study highlights the critical role of base excision repair enzymes, specifically OGG1, in ROS-induced cell death.
- Combining lower doses of ROS-inducing agents with MTH1 inhibitors presents a potentially more selective and safer chemotherapeutic strategy for cervical cancer.
- Targeting DNA repair pathways offers a promising avenue for novel cervical cancer treatments.
More Related Videos
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...