Elevated oxidative stress is a hallmark of cancer, as it promotes cell proliferation through rewiring metabolism and signalling. Here, I asked whether perturbing redox balance could inhibit cancer cell proliferation and enhance the efficacy of antimitotic drugs.

I found that conditional knockout of Superoxide Dismutase 2 (SOD2), a key mitochondrial redox defence protein, resulted in abolition of proliferation in HeLa cells. This contradicts previous studies establishing that SOD2 is non-essential in cell line and mouse models. SOD2 turn-off resulted in an increased ROS level and a reduction of cell proliferation. Although cell cycle arrest was not observed, I noticed a mitotic entry delay due to DNA damage. Inhibition of DNA damage repair pathway by PARP inhibition further exacerbate t...[ Read more ]

Elevated oxidative stress is a hallmark of cancer, as it promotes cell proliferation through rewiring metabolism and signalling. Here, I asked whether perturbing redox balance could inhibit cancer cell proliferation and enhance the efficacy of antimitotic drugs.

I found that conditional knockout of Superoxide Dismutase 2 (SOD2), a key mitochondrial redox defence protein, resulted in abolition of proliferation in HeLa cells. This contradicts previous studies establishing that SOD2 is non-essential in cell line and mouse models. SOD2 turn-off resulted in an increased ROS level and a reduction of cell proliferation. Although cell cycle arrest was not observed, I noticed a mitotic entry delay due to DNA damage. Inhibition of DNA damage repair pathway by PARP inhibition further exacerbate the extent of DNA damage and cell death. This suggests that persistent DNA damage undermines the survival of SOD2^KO cells and points to synergy between co-inhibition of redox defence and DNA damage repair pathways.

Prolonged mitotic block can cause various outcomes, including apoptosis and mitotic slippage. While the role of Spindle Assembly Checkpoint (SAC) and apoptotic proteins in determining mitotic cell fate has been extensively studied, the involvement of redox regulation remains largely unexplored. I showed that Reactive Oxygen Species (ROS) levels decreased during prolonged mitotic arrest, but ectopic ROS treatment, by either H₂O₂ or SOD2 conditional knockout promoted cell death. Conversely, antioxidants treatment by N-Acetyl Cysteine (NAC) or SOD2 overexpression promoted defective mitotic exit without delaying cell death. Interestingly, caspase inhibitor treatment only partially delayed cell death, suggesting unknown redox-dependent mechanisms may regulate mitotic cell death. These data suggest that redox homeostasis regulates fates during mitotic arrest.