Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway

Avnet, S, Chano, T, Massa, A, Bonuccelli, G, Lemma, S, Falzetti, L, Grisendi, G, Dominici, M and Baldini, N 2019, 'Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway' , American journal of cancer research, 9 (6) , pp. 1127-1144.

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Abstract

Extracellular acidification is a very common cause of stress in tumor microenvironment and of Darwinian pressure. In acid areas of the tumor, most cancer cells are-albeit slowly proliferating-more resistant to cell death than those in well-perfused regions. Tumor acidosis can directly regulate the expression of pro-survival proteins since a low extracellular pH activates the caspase-dependent cell death machinery. This mechanism has never been explored in bone sarcomas. We cultured osteosarcoma and Ewing sarcoma cells under low pH (pH 6.5), and we performed deep-sequencing and protein analysis. Both in in vitro and in vivo models, acidification activity enhanced tumor cells survival. However, we did not observe any change in ERK1 phosphorylation. On the contrary, both at the mRNA and protein level, we found a significant induction of TRAF adaptor proteins and of cIAP proteins (BIRC2 and/or BIRC3). As a consequence, the downstream nuclear transcription factor kappa B (NF-κB) survival pathway was increased. Furthermore, the treatment with the cIAP inhibitor LCL161 reverted the protection from apoptosis under low pH. In vitro results were confirmed both in Ewing sarcoma xenograft and in osteosarcoma patients, since the analysis of tumor tissues demonstrated that the levels of expression of TRAF1 or NF-κB1 significantly correlate with the level of expression of the vacuolar ATPase (V-ATPase), the most important proton pump in eukaryotes. Moreover, in the tissue sections of xenograft model, the nuclear translocation of RelB, a key subunit of the NF-κB transcriptional complex, localized in the tumor region that also corresponded to the acid microenvironment associated with the highest levels of expression of LAMP2 and V-ATPase, in the internal area of the tumor, as revealed by immunohistochemistry. Our data confirm that tumor acid microenvironment activates a stress-regulated switch to promote cell survival of bone sarcoma, and support the hypothesis that this mechanism is mediated by the recruitment of TRAF/cIAP complexes. Altogether, these results suggest that TRAF/cIAP can be considered as a target for anti-cancer therapies.

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router **Journal IDs: pissn 2156-6976 **Article IDs: pmc: PMC6610055 **History: accepted 28-01-2019; submitted 23-07-2018
Uncontrolled Keywords: BIRC/TRAF pathway, Bone sarcoma, acid tumor microenvironment, cell survival
Schools: Schools > School of Environment and Life Sciences
Journal or Publication Title: American journal of cancer research
Publisher: e-Century Publishing
ISSN: 2156-6976
Related URLs:
Funders: Natural Science Foundation of Shandong Province, Clinical Medicine + X Project of Qingdao University
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 09 Dec 2019 12:37
Last Modified: 09 Dec 2019 12:45
URI: http://usir.salford.ac.uk/id/eprint/51860

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