Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer thera
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Cellular and Molecular Life Sciences
VISIONS AND REFLECTIONS
Oncogenic pathways activated by pro‑inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies Gabriella D’Orazi1 · Marco Cordani2 · Mara Cirone3 Received: 25 May 2020 / Revised: 3 September 2020 / Accepted: 6 October 2020 © Springer Nature Switzerland AG 2020
Abstract Inflammation and cancerogenesis are strongly interconnected processes, not only because inflammation promotes DNA instability, but also because both processes are driven by pathways such as NF-kB, STAT3, mTOR and MAPKs. Interestingly, these pathways regulate the release of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β that in turn control their activation and play a crucial role in shaping immune response. The transcription factor p53 is the major tumor suppressor that is often mutated in cancer, contributing to tumor progression. In this overview, we highlight how the interplay between proinflammatory cytokines and pro-inflammatory/pro-oncogenic pathways, regulating and being regulated by UPR signaling and autophagy, affects the stability of mutp53 that in turn is able to control autophagy, UPR signaling, cytokine release and the activation of the same oncogenic pathways to preserve its own stability and promote tumorigenesis. Interrupting these positive feedback loops may represent a promising strategy in anticancer therapy, particularly against cancers carrying mutp53. Keywords Inflammatory cytokines · Cancer · Mutant p53 · Unfolded protein response · Oncogenic pathways · Autophagy
Introduction Pro-inflammatory and anti-inflammatory cytokines such as IL-6, IL-1β, TNF-α and IL-10 deeply shape immune response; therefore the dysregulation of their production may lead to immune dysfunction, favoring the onset of inflammatory diseases including cancer [1–3]. NF-kB (nuclear factor kappa-light chain- enhancer of activated B cells), MAPKs (mitogen-activated protein kinases), mTOR (mammalian target of rapamycin) and STAT3 (signal transducer and activator of transcription 3) are among the most important pathways that regulate cytokine production and, interestingly, also strongly involved in the control of carcinogenesis. These pathways that bridge inflammation to cancer may be activated in response to cellular stress caused by the * Mara Cirone [email protected] 1
Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
2
IMDEA Nanociencia, C/Faraday 9, Ciudad Universitaria de Cantoblanco, Madrid, Spain
3
Department of Experimental Medicine, Laboratory Affiliated to Pasteur Institute Italy Foundation Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
presence of oncogenes or by the sensing of PAMPs (pathogens-associated molecular patterns) or DAMPs (damageassociated molecular patterns), molecules that also trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) [4]. UPR is an adaptive response that helps cells to survive in the face of stress
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