Fig 5.

The accumulation of ROS causes cancer cell apoptosis. Accumulated-ROS induce DNA damage, thus causing the activation of ATM and ATR, and activating P53. Abundant ROS reactivate mutant P53 protein, and P53 subsequently promotes the expression of pro-apoptotic proteins, BAX, MDM2 and Puma, thus subsequently leading to cancer cell apoptosis. ROS oxidize cardiolipin, thereby resulting in Cyt c detachment from the membrane. Oxidized cardiolipin translocates to the outer membrane and recruits the pro-apoptotic protein BAX to the mitochondrial membrane, thus enhancing MOMP and generating Cyt c-traversable pores. ROS also activate ASK/JNK and ASK/P38 axis and promote the release of Cyt c in a manner dependent on BAX. Cyt c interacts with Apaf-1, thus resulting in apoptosome formation, leading to caspase-9 and caspase-3/7 activation, and causing cancer cell apoptosis. The accumulation ROS also causes cancer cell apoptosis via the ER stress pathway through the PERK/eIF2α/ATF-4/CHOP axis and IRE1α/JNK/CHOP axis. MDM 2, murine double minute 2; Puma, p53 upregulated modulator of apoptosis; Apaf1, apoptotic protease activating factor 1; PERK, protein kinase-like ER kinase; IRE1α, inositol-requiring enzyme-1α; ATF4, activating transcription factor-4.