A surprising mediator of oxidative DNA damage

KEYWORDS :

• cell death
• chemotherapy
• DNA damage
• dsDNA breaks
• Endoplasmic Reticulum stress
• Leukotriene C4
• microsomal glutathione-S-transferase 2
• NADPH oxidase 4
• Oxidative stress
• reactive oxygen species

This article refers to:

Endoplasmic reticulum (ER) stress and major chemotherapeutic agents damage DNA by generating reactive oxygen species (ROS). We recently reported that ER stress and major chemotherapeutic agents induce leukotriene C₄ (LTC₄) biosynthesis in cells of non-haematopoietic lineage.¹ ER stress or chemotherapy activate LTC₄ biosynthetic machinery by assembly at the nuclear envelope of microsomal glutathione-S-transferase 2 (MGST2), 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and cytoplasmic phospholipase A2 (cPLA2). ER stress and chemotherapy also trigger nuclear translocation of the two LTC₄ receptors, CysLTR1 & CysLTR2. Acting in an intracrine manner, LTC₄ then elicits nuclear translocation of NADPH oxidase 4 (NOX4), resulting in nuclear ROS accumulation, oxidative DNA damage and dsDNA breaks. MGST2 deficiency, RNAi and LTC₄ receptor antagonists abolished ER stress- and chemotherapy-induced ROS accumulation and DNA damage in vitro and in mouse kidneys. Notably, acting as a CysLTR1 antagonist, the approved asthma drug pranlukast abolished doxorubicin-triggered DNA damage. Cell death and mouse morbidity were also significantly attenuated (Fig. 1). Hence, we concluded that MGST2-generated LTC₄ is the major mediator of ER stress- and chemotherapy-triggered oxidative stress and oxidative DNA damage, thereby augmenting cell death. Tumor cells of haematopoietic origin do not express MGST2. Indeed, they remained sensitive to chemotherapy in the presence of LTC₄ inhibitors. We therefore propose that LTC₄ inhibitors, commonly used for the treatment of asthma, may alleviate chemotherapy-associated morbidities when used in hematologic malignancies. In addition, our findings provide the possible mechanism by which these asthma drugs attenuated the neurotoxicity of amyloid β peptide – the suspected trigger of Alzheimer's disease, damage to heart myocytes by hypoxia-reperfusion as happens in myocardial infraction and gentamycin-triggered kidney damage.^2-4 NOX4 has also been implicated in these and additional major human pathologies, including metabolic diseases, neurodegeneration and osteoporosis.^5-7 Therefore, inhibition of its activation by LTC₄ receptor antagonists, already serving as approved asthma drugs, may have broad clinical significance.

Figure 1. The stress-triggered signaling pathway leading to DNA damage and cell death.

Abbreviations

cPLA2	=	cytoplasmic phospholipase A2
CysLTR1 & CysLTR2	=	the 2 LTC4 receptors
ER	=	endoplasmic reticulum
FLAP	=	5-LO activating protein
5-LO	=	5-lipoxygenase
LTC4	=	leukotriene C4
MGST2	=	microsomal glutathione-S-transferase 2
NOX4	=	NADPH oxidase 4
ROS	=	reactive oxygen species