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Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588
Jia Yu Wang1, Lei Jin2, Xu Guang Yan1
1School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
Abstract:
The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS.
Insights
The MTH1 inhibitor TH588 kills melanoma cells by inducing apoptosis via reactive oxygen species (ROS), not by inhibiting MTH1. MTH1 inhibition alone does not affect cell survival but sensitizes cells to oxidative stress.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- MTH1 (NUDT1) is a key enzyme in preventing oxidative DNA damage.
- The role of MTH1 inhibition in cancer cell survival remains unclear.
- TH588 is a first-in-class inhibitor targeting MTH1.
Purpose of the Study:
- To investigate the mechanism of TH588-induced cytotoxicity in melanoma cells.
- To determine if MTH1 inhibition is responsible for TH588's anti-cancer effects.
- To explore the role of reactive oxygen species (ROS) in TH588's action.
Main Methods:
- Silencing and overexpression of MTH1 in melanoma cells.
- Treatment with TH588, elesclomol (oxidative stress inducer), ROS scavengers, and antioxidants.
- Assessment of apoptosis induction and cell viability.
- Correlation analysis between TH588 sensitivity and endogenous ROS levels.
Main Results:
- MTH1 silencing did not affect melanoma cell survival.
- TH588 induced apoptosis independently of MTH1 inhibition, even with bacterial MTH1 homolog expression.
- MTH1 knockdown sensitized cells to elesclomol-induced apoptosis.
- TH588-induced apoptosis was enhanced by elesclomol and attenuated by ROS scavengers/antioxidants.
- Melanoma cell sensitivity to TH588 correlated with endogenous ROS levels.
Conclusions:
- TH588's cytotoxicity in melanoma is mediated by ROS production, not MTH1 inhibition.
- MTH1 inhibition alone does not cause cell death but can sensitize cells to oxidative stress.
- Targeting ROS pathways may be crucial for TH588 efficacy in melanoma treatment.
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