P53 versus inflammation: an update

ABSTRACT

Etiologies of human pathophysiology have been associated with states of severe inflammation. The endothelium defender P53 supports cellular functions, by orchestrating anti-inflammatory responses. The purpose of the present article is to provide an update on the mechanisms enforcing the protective actions of P53 in human homeostasis, and to discuss current efforts on the development of new therapies against inflammatory abnormalities.

KEYWORDS:

• Barrier function
• endothelium
• growth hormone releasing hormone

P53

Wild type P53 is a transcription factor which protects the genome against environmental and intracellular challenges [1]. Although P53 was initially considered to be an oncogene, it was later discovered that those properties were associated with the suppression of tumors [2]. Thus, this protein was named “The Guardian of the Genome”, and has been thoroughly investigated due to his multifaceted protective activities toward cellular prevalence [3]. The capacity of P53 to counteract “malicious” threats, capacitated intense investigations on the exact role of that protein in cellular defense. The further understanding of those activities, may pioneer novel strategies to fight inflammation-related manifestations of human disease.

The latest advances in the field of molecular biology, suggest that certain malignancies arise upon severely injured inflammatory sites, transformed to carcinogenetic niche. Indeed, P53 is associated with anti-inflammatory activities, which in turn are employed to suppress immature carcinogenetic sites [4]. Oncogenic stimuli tend to suppress P53, while robust anti-cancer agents aim to augment the activities of that tumor suppressor.

Growth Hormone Releasing Hormone (GHRH) and P53

GHRH is a hypothalamic peptide, which regulates the release of growth hormone from the anterior pituitary gland [5]. An emerging body of evidence suggests that it acts as a growth factor in human malignancies [6]. Treatment of the most lethal human cancers with GHRH, potentiated their proliferation rate and metastatic potential [7]. Those effects; have been associated with the suppression of P53 [8]. In bold contrast, GHRH antagonists are strong P53 inducers associated with prominent anti-inflammatory activities in cancerous and non-cancerous tissues [9], including the lung endothelium [8,10].

It was recently shown both in vivo and in vitro that GHRH antagonists may enhance the lung endothelium integrity via multiple pathways [11], by suppressing the RhoA pathway, as well as by sabotaging cofilin. Moreover, those compounds corrupted the activation of kinases, responsible for streaming inflammatory events [12]. Those outcomes revealed a possible new therapeutic strategy against Acute Lung Injury, and its most severe form, the lethal Acute Respiratory Distress Syndrome (ARDS).

Heat Shock Protein (HSP) 90 inhibition and P53

Hsp90 inhibition, may represent another alternative strategy to help those hospitalized patients subjected to such respiratory abnormality, namely ARDS. Hsp90 is a molecular chaperone, which assists the maturation and the correct folding of the plethora of intracellular proteins, major players in streaming inflammatory responses. The inhibition of those activities have been shown to oppose the development of cancers, and to disorganize inflammatory responses [13]. Furthermore, both in vivo and in vitro, those compounds have been shown to counteract the Lipopolysaccharides (LPS) – inflicted lung injury in bovine and human microvascular endothelial cells [14]. Those effects are due to the reorganization of the actin cytoskeleton, the modulation of major inflammatory kinases, as well as the regulation of the Rho GTPases in charge of endothelial permeability [15]. The inhibition of the RhoA/MLCII pathway by Hsp90 inhibition sabotage the F actin formation due to LPS, suppressing hyperpermeability responses which endanger the normal respiratory function [14]. The deactivation of the actin-destroyer cofilin by Hsp90 inhibition, exerts similar protective effects in the lung physiology [16]. Both events, have been associated with the “Endothelium Defender” [17].

The post-translational modifications of P53 have been shown to trigger inflammatory responses, and the phosphorylation of that transcription factor is a LPS-triggered event. The reversal of that alteration by Hsp90 inhibition, contributes to the supportive activities of those compounds toward the vasculature [18]. Moreover, Hsp90 inhibitors induce the expression of P53, as well as its association with Hsp90 [19]. It appears that the inflammatory factor and redox regulator APE1/Ref1 participates in those phenomena, and it is subjected to regulation by P53. Upregulation of P53 has been associated with APE1/Ref1 reduction, while suppression of P53 exerted the opposite effects [20]. Those observations, imply that the anti-inflammatory activities of P53 in the lung vasculature are probably associated with modulation of the reactive oxygen species production (ROS).

ROS and P53

By reducing APE1/Ref1, P53 dictates the suppression of ROS generation. The P53-mediated reduction of ROS has been previously shown in prostate cancer cells, by employing GHRH antagonists as P53 inducers [10]. Another study has recently demonstrated that the antioxidant activities of P53 in the human blood brain barrier is strongly connected to the reduction of the malondialdehyde, which is considered a marker of lipid oxidation [21].

Unfolded protein response and P53

The reduction of the reactive oxygen species in the cells may occur due to the induction of the unfolded protein response (UPR) [22]. This is a synergy of mechanisms, which are destined to activate a diverse network of cellular repairing activities in response to certain signals [23]. It is consisted of the inositol requiring enzyme-1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-like endoplasmic reticulum kinase (PERK) [24]. Those molecules serve as sensors of potential threats, and are responsible for devising counteracting measures. If they fail to successfully orchestrate survival responses, they will eventually kill the cells [25]. A robust UPR induction has been associated with enhancing inflammatory responses [26]. On the other hand, upon mild induction, certain elements of UPR (i.e. ATF6), oppose inflammation and drive repairing mechanisms [27]. An interesting study showed that UPR induction induces P53, while suppression of that multi-branch mechanism resulted to the suppression of that transcription factor. The exacts mechanism responsible for that regulation are to be elucidated [28].

Future directions

In our opinion, the exciting research topic of the role of P53 in inflammation is intriguing. The mechanisms by which P53 counteracts inflammation, as well as the ways by which inflammation encounter P53 are still not completely understood. Future studies shall focus on the elucidation of the mechanisms which govern the fascinating topic of the anti-inflammatory role of P53 toward human tissues, including the lung endothelium. Moreover, we believe that the exploration of the exact relations between the different UPR components and P53 shall drive the discoveries of novel therapeutic targets in diseases strongly associated with inflammatory states, such as ARDS and cancer.

Acknowledgments

Dr. Barabutis’ is supported by 1) R&D, Research Competitiveness Subprogram (RCS) of the Louisiana Board of Regents through the Board of Regents Support Fund (LEQSF(2019-22)-RD-A-26) 2) NIGMS/NIH (5 P20GM103424-15, 3 P20GM103424-15S1) 3) Faculty Research Support Program of the College of Pharmacy, University of Louisiana Monroe, Monroe LA 71201 4) Malcolm Feist Partners Across Campuses Seed Program of the Center for Cardiovascular Diseases and Sciences, LSU Health Shreveport, Shreveport, LA 71103.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by R&D, Research Competitiveness Subprogram (RCS) of the Louisiana Board of Regents through the Board of Regents Support Fund (LEQSF(2019-22)-RD-A-26); National Institute of General Medical Sciences / National Institute of Health [5 P20GM103424-15, 3 P20GM103424-15S1]; Faculty Research Support Program of the College of Pharmacy, University of Louisiana Monroe, Monroe LA 71201; Malcolm Feist Partners Across Campuses Seed Program, Center for Cardiovascular Diseases and Sciences, LSU Health Shreveport, Shreveport, LA 71103.