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PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Swindall AF, Stanley JA, Yang ES - Cancers (Basel) (2013)

Bottom Line: Interestingly, PARP is highly expressed in several human cancers.Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules.Thus, the upregulation of PARP may present a double-edged sword.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249, USA. eyang@uab.edu.

ABSTRACT
Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

No MeSH data available.


Related in: MedlinePlus

Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts a co-activator of NFkB signaling, which can propogate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively-clustered DNA lesions (OCDLs). The formation of OCDLs have been shown to be elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.
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cancers-05-00943-f002: Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts a co-activator of NFkB signaling, which can propogate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively-clustered DNA lesions (OCDLs). The formation of OCDLs have been shown to be elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.

Mentions: The principle behind PARP inhibitor treatment of familial cancers deficient in homologous recombination (HR) repair is that by inhibiting the BER pathway in conjunction with endogenous failure of the HR pathway, the cell will be incapable of repairing DNA damage leading to cell death. However, our lab has demonstrated that PARP-1 inhibition also kills HER2+ breast cancer cells despite proficient HR repair, indicating PARP-1 may be an effective treatment for non-familial, sporadic cancers as well as familial cancers [61]. Interestingly, we found that susceptibility of non-familial cancers to PARP-1 inhibition may be through altered NFκB signaling [61]. While the mechanisms behind this are not yet determined, it does provide evidence that the applications of PARP-1 inhibitors in the treatment of cancers may be further extended than originally thought. Therefore, it may be possible to use of PARP-1 inhibitors to not only treat familial cancers, but also to treat and even prevent cancers of non-familial origin, especially cancers associated with chronic inflammation. Chronic PARP-1 activation in tissues undergoing high metabolic activity or tissues subjected to continual ROS-induced stress may be at increased risk for developing cancer driven by PARP-1 signaling, which may be the case for the study in hepatocellular carcinoma mentioned previously which show elevated PARP-1 levels in cirrhotic patients [62]. Together this points to PARP inhibition as an attractive target not only for familial cancers, but also as a treatment, and potentially a preventative agent, for cancers in tissues or organs experiencing chronic ROS-induced damage or high levels of metabolism. A schematic of this potential divergent role of PARP-1 is shown in Figure 2.


PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Swindall AF, Stanley JA, Yang ES - Cancers (Basel) (2013)

Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts a co-activator of NFkB signaling, which can propogate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively-clustered DNA lesions (OCDLs). The formation of OCDLs have been shown to be elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3795373&req=5

cancers-05-00943-f002: Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts a co-activator of NFkB signaling, which can propogate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively-clustered DNA lesions (OCDLs). The formation of OCDLs have been shown to be elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.
Mentions: The principle behind PARP inhibitor treatment of familial cancers deficient in homologous recombination (HR) repair is that by inhibiting the BER pathway in conjunction with endogenous failure of the HR pathway, the cell will be incapable of repairing DNA damage leading to cell death. However, our lab has demonstrated that PARP-1 inhibition also kills HER2+ breast cancer cells despite proficient HR repair, indicating PARP-1 may be an effective treatment for non-familial, sporadic cancers as well as familial cancers [61]. Interestingly, we found that susceptibility of non-familial cancers to PARP-1 inhibition may be through altered NFκB signaling [61]. While the mechanisms behind this are not yet determined, it does provide evidence that the applications of PARP-1 inhibitors in the treatment of cancers may be further extended than originally thought. Therefore, it may be possible to use of PARP-1 inhibitors to not only treat familial cancers, but also to treat and even prevent cancers of non-familial origin, especially cancers associated with chronic inflammation. Chronic PARP-1 activation in tissues undergoing high metabolic activity or tissues subjected to continual ROS-induced stress may be at increased risk for developing cancer driven by PARP-1 signaling, which may be the case for the study in hepatocellular carcinoma mentioned previously which show elevated PARP-1 levels in cirrhotic patients [62]. Together this points to PARP inhibition as an attractive target not only for familial cancers, but also as a treatment, and potentially a preventative agent, for cancers in tissues or organs experiencing chronic ROS-induced damage or high levels of metabolism. A schematic of this potential divergent role of PARP-1 is shown in Figure 2.

Bottom Line: Interestingly, PARP is highly expressed in several human cancers.Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules.Thus, the upregulation of PARP may present a double-edged sword.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249, USA. eyang@uab.edu.

ABSTRACT
Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

No MeSH data available.


Related in: MedlinePlus