Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer

Abstract

Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer.

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

“…30 From such perspective, it appears worth investigating if cancer cells scavenge PON1 from the circulation to exploit its anti-oxidative effect for cell death escape. Generally, such a hypothesis might be supported by studies linking PON1 genotypes, for example, to renal carcinomas, breast, ovarian and prostate cancer (as reviewed elsewhere 31 ). However, it yet remained uncertain which function of PON1 was of major importance, its hydrolytic activity or anti-oxidative effect.…”

The contribution of paraoxonase 1 and myeloperoxidase to HDL-cholesterol functionality

“…Early studies have indicated that both human and animal PON1 is closely associated with the HDL-C fraction, and this interaction is stabilised by the apolipoprotein A-I [9,39,47]. PON1 is essential for the antioxidative HDL-C protection of LDL-C [92]. On the other hand, in vitro studies have demonstrated that oxLDL-C, as well as other oxidised lipoproteins, markedly decrease the PON1 activity, thus bringing about HDL-C dysfunctionality [8].…”

“…However, at present it seems that both play an important role in the body's protection against atherosclerosis and systemic inflammation, but also against cancer [22,84,92].…”

Modulation of cell death signaling and cell proliferation by the interaction of homoserine lactones and Paraoxonase 2.

“…An emerging strategy for cancer therapy is to overcome the resistance to apoptosis caused by aberrant Bcl-2 signaling in tumor cells (96,97). Recently, several small molecules triggering apoptosis independent of either pro-or anti-apoptotic Bcl-2 proteins have been It has been reported that lung tumor cells are resistant to conventional therapeutic drugs partially due to enhanced expression of PON2, which is thought to be associated with anti-oxidant activities of PON2 (78,79). Data presented in Figure 3.13 show decreased killing of A549 and NCI-H1299 cells with shRNA for PON2; which is consistent with previous results (9).…”

“…PON2 is upregulated in many types of cancer, including lung cancer, enabling cancer cells to resist conventional therapeutic drugs (78,79). PON2 expression also prevents NHBE and hT/LT/Ras cells were grown in BEGM supplemented with SingleQuots (LONZA).…”