The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics

Abstract

Chronic infection by high-risk human papillomaviruses (HPV) and chronic inflammation are factors associated with the onset and progression of several neoplasias, including cervical cancer. Oncogenic proteins E5, E6, and E7 from HPV are the main drivers of cervical carcinogenesis. In the present article, we review the general mechanisms of HPV-driven cervical carcinogenesis, as well as the involvement of cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) and downstream effectors in this pathology. We also review the evidence on the crosstalk between chronic HPV infection and PGE₂ signaling, leading to immune response weakening and cervical cancer development. Finally, the last section updates the current therapeutic and preventive options targeting PGE₂-derived inflammation and HPV infection in cervical cancer. These treatments include nonsteroidal anti-inflammatory drugs, prophylactic and therapeutical vaccines, immunomodulators, antivirals, and nanotechnology. Inflammatory signaling pathways are closely related to the carcinogenic nature of the virus, highlighting inflammation as a co-factor for HPV-dependent carcinogenesis. Therefore, blocking inflammatory signaling pathways, modulating immune response against HPV, and targeting the virus represent excellent options for anti-tumoral therapies in cervical cancer.

Keywords: cervical cancer; cervical cancer treatment; chronic inflammation; cyclooxygenase-2; human papillomavirus; oncogenic proteins; prostaglandin E2.

Figure 1

Role of P53 on normal cell physiology and during high-risk HPV infection. (a) In the absence of stressors, the coordinated action of MDM2 and proteasome maintain very low P53 bioavailability. (b) Stressor factors such as nutrient deprivation, genotoxic damage, and abnormal expression of oncogenes inhibit MDM2 activity while other cellular factors stabilize P53 by post-translational modification such as phosphorylation and acetylation. Acting as a homotetramer, P53 activates genes favoring DNA repair, apoptosis, and cell cycle arrest, among other processes involved in tumor development prevention. (c) Epithelial cells infected with HPV produce high levels of E6 oncogene, which binds E6AP. The complex E6AP-E6 targets P53 for degradation in the proteasome. Using this mechanism, E6 suppresses the protective response initiated by P53 against HPV infection. ub, ubiquitin; P, phosphorylation; Ac, acetylation.

Figure 2

PGE₂ biosynthesis. Arachidonic acid (AA) is released from membrane phospholipids by cytoplasmic phospholipase A2 (PLA₂). The cyclooxygenase (COX) enzymes COX-1 and COX-2 convert AA to prostaglandin G2 (PGG₂) and then prostaglandin H2 (PGH₂). Subsequently, the enzyme PGE₂ synthase (PGES) converts PGH₂ to prostaglandin E2 (PGE₂).

Figure 3

PGE₂ activates four receptors, PTGER1-4. Prostaglandin E₂ (PGE₂) binds to G protein-coupled receptors identified as PTGER1-4. The binding of PGE₂ to PTGER1 causes the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) in the Gαq subunit allowing its dissociation from the βγ complex. The α subunit moves to phospholipase C (PLC) and activates it. This enzyme catalyzes the cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP₂) to produce two intracellular second messenger diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 binds to specific calcium (Ca²⁺) channels releasing Ca²⁺ into the cytosol. Both IP3 and DAG contribute to activating protein kinase C (PKC). Regarding PTGER2 and PTGER4, the activation of adenylate cyclase (AC) by Gαs causes an increase in the intracellular cyclic adenosine monophosphate (cAMP) concentration formed from adenosine triphosphate (ATP). In contrast, the binding of PGE₂ to PTGER3 causes inhibition of the activity of AC, resulting in diminished production of cAMP through the Gαi subunit. The activation of PTGER receptors regulates many cellular processes.

Figure 4

Crosstalk between HPV infection and PGE₂ signaling on cancer progression. Cervical neoplasia may be promoted by HPV infection or chronic inflammation, processes that greatly interact to fuel tumorigenesis. HPV viral oncoproteins E5, E6 and E7 produce chronic inflammation by up-regulating COX-2 expression and consequently prostaglandin E2 (PGE₂) production. HPV may also induce other inflammatory mediators such as reactive oxygen and nitrogen species (ROS, RNS), and PGE₂ receptors (PTGER) expression. Likewise, PTGER activation results in increased expression/release of inflammatory cytokines (ICs) and metalloproteinases, as well as COX-2 activity/expression. Notably, ROS and RNS may cause DNA damage, facilitating HPV–DNA integration. Another important oncogenic mechanism in cervical HPV-dependent neoplasia is immune response evasion. Viral oncoproteins can drive dendritic cells (DCs) and lymphocytes towards a protolerogenic phenotype, inhibiting the expression of Toll-like receptor 9 (TLR9), down-regulating ICs such as interferon-gamma (IFNγ) while up-regulating immunosuppressive cytokines, including interleukin-10 (IL-10) and transforming growth factor beta (TGFβ), allowing HPV to survive. Furthermore, increased inflammatory mediators were associated with the induction of immunosuppressive myeloid-derived suppressor cells (MDSCs). Finally, known signaling pathways involved in the crosstalk between HPV infection and inflammation include PI3K/AKT, the epidermal growth factor receptor (EGFR)/nuclear factor-kappa B (NF-κB), COX-2/PGE₂/PTGERs, and the cyclic AMP (cAMP)/cAMP-response element binding protein (CREB)/cAMP-responsive element (CRE).