Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities

Rajawat, Jyotika; Shukla, Nidhi; Mishra, Durga Prasad

doi:10.1002/med.21442

Cited by 52 publications

(40 citation statements)

References 158 publications

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“…Interestingly, the role of PARP1 in the regulation of autophagy is controversial. Both autophagy inductor [70][71][72] and inhibitor [73][74][75] role of PARP1 has been described suggesting that the autophagy-modulatory effect of PARylation might show DNA damage and cell type specificity. Even though, we detected an increased number of LC3 puncta, this type of macroautophagy cannot be considered as mitophagy since autophagic puncta show very mild colocalization with mitochondria ( Figure 5D).…”

Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM. IntroductionMitochondria regulate their shape, number, distribution, mass, content of mitochondrial DNA (mtDNA), and metabolic capacity in a process called mitochondrial biogenesis, which requires the orchestration of complex transcriptional control of both nuclear and mitochondrial genes [1,2]. The function of mitochondrial biogenesis is to provide quality control of mitochondria by regulating mitochondrial fission, fusion, and mitophagy [3,4] to maximize the energy utilization of mitochondria [5] to meet cellular and environmental demands. Imbalances or perturbations in these processes can lead to mitochondrial dysfunction [3,6].Accumulating evidence suggests that mitochondria also play a central role in skin physiology. Although, involvement of other organ systems predominates in classical mitochondrial disorders, several cutaneous diseases can be linked to mitochondrial dysfunctions [7]. Interestingly, mitochondria lack functional nucleotide excision repair (NER) pathway [8,9] which is responsible for the removal of ultraviolet (UV)-induced DNA lesions including cyclobutane pyrimidine dimers (CPD). Accumulation of these DNA photoproducts in mtDNA leads to mutations and deletions resulting in mitochondrial alterations which have been associated with photoaging [10,11] and are present in melanoma [12], as well as in non-melanoma skin cancers [13,14]. The other types of mitochondrial alterations such as upregulated oxidative phosphorylation (OXPHOS), mitochondrial memb...

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Section: Parp Inhibition and Uvb Induces Bulk Autophagy But Not Mitopmentioning

confidence: 99%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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“…However, by showing that continuously active Akt rescued these cells [12], we demonstrated that the said synthetic lethality is predominantly resulted from insufficient Akt activation in ATM suppressed cells. These data emphasize the crucial importance of Akt activation in PARP1 inhibition's cytoprotective property that can lead to undermining PARP1 inhibition's cytostatic effect on breast cancer gene (BRCA) mutations carrying cancers [110]. Independent reports support this notion by demonstrating the increase of PARP1 inhibitors' cytotoxicity by Akt inhibitors [8,11,111].…”

Section: Mechanism Of Parp Inhibition Induced Akt Activationmentioning

confidence: 83%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

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Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

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“…Whilst progress has been made, these inhibitors are not efficient tools for gaining detailed information on the role of PARP1 in cellular responses to DNA insults, due in part to their side effects and interference with other pathways unrelated to PARP1 [33]. Nevertheless, specific PARP inhibitors have been developed for disease treatment in clinics [11,14,15,34,35]. The main knowledge about the biology of PARP1 and PARylation comes from mutagenesis studies of the enzyme using cellular and animal experimental systems.…”

Section: Biological Functions Of Parp1mentioning

confidence: 99%

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

Kamaletdinova

Fanaei-Kahrani

Wang

2019

Cells

106

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Poly(ADP-ribosyl)ation (PARylation) is catalysed by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) and then rapidly removed by degrading enzymes. Poly(ADP-ribose) (PAR) is produced from PARylation and provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. The PARylation system, consisting of PAR synthesizers and erasers and PAR itself and readers, plays diverse roles in the DNA damage response (DDR), DNA repair, transcription, replication, chromatin remodeling, metabolism, and cell death. Despite great efforts by scientists in biochemistry, cell and molecular biology, genetics, and pharmacology over the last five decades, the biology of PARPs and PARylation remains enigmatic. In this review, we summarize the current understanding of the biological function of PARP1 (ARTD1), the founding member of the PARP family, focusing on the inter-dependent or -independent nature of different functional domains of the PARP1 protein. We also discuss the readers of PAR, whose function may transduce signals and coordinate the cellular processes, which has recently emerged as a new research avenue for PARP biology. We aim to provide some perspective on how future research might disentangle the biology of PARylation by dissecting the structural and functional relationship of PARP1, a major effector of the PARPs family.

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Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities

Cited by 52 publications

References 158 publications

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

The Enigmatic Function of PARP1: From PARylation Activity to PAR Readers

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