Cancer-derived immunoglobulin G promotes tumor cell growth and proliferation through inducing production of reactive oxygen species

Abstract

Cancer cells have been found to express immunoglobulin G (IgG), but the exact functions and underlying mechanisms of cancer-derived IgG remain elusive. In this study, we first confirmed that downregulation of IgG restrained the growth and proliferation of cancer cells in vitro and in vivo. To elucidate its mechanism, we carried out a co-immunoprecipitation assay in HeLa cells and identified 27 potential IgG-interacting proteins. Among them, receptor of activated protein kinase C 1 (RACK1), ras-related nuclear protein (RAN) and peroxiredoxin 1 (PRDX1) are closely related to cell growth and oxidative stress, which prompted us to investigate the mechanism of action of IgG in the above phenomena. Upon confirmation of the interactions between IgG and the three proteins, further experiments revealed that downregulation of cancer-derived IgG lowered levels of intracellular reactive oxygen species (ROS) by enhancing cellular total antioxidant capacity. In addition, a few ROS scavengers, including catalase (CAT), dimethylsulfoxide (DMSO), n-acetylcysteine (NAC) and superoxide dismutase (SOD), further inhibited the growth of IgG-deficient cancer cells through suppressing mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) signaling pathway induced by a low level of intracellular ROS, whereas exogenous hydrogen peroxide (H2O2) at low concentration promoted their survival via increasing intracellular ROS levels. Similar results were obtained in an animal model and human tissues. Taken together, our results demonstrate that cancer-derived IgG can enhance the growth and proliferation of cancer cells via inducing the production of ROS at low level. These findings provide new clues for understanding tumor proliferation and designing cancer therapy.

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

“…The role of physiological ROS as a signalling molecule in key signalling pathways (D'Autréaux and Toledano, 2007) including proliferation (Ruiz-Ginés et al, 2000;Valarde et al, 2004;Lister et al, 2011;Wang et al, 2013) has been shown in a number of studies. In order to illustrate that physiological ROS might be involved in maintaining high growth rates, a cellular proliferation assay was performed in the presence of 10 mM NAC.…”

Cancer Metabolic and Immune Reprogramming: The Intimate Interaction Between Cancer Cells and Microenvironment

“…It seems that IgG can enhance the growth and proliferation of tumor cells via inducing the production of ROS at low level. These findings provide new clues for understanding tumor proliferation and designing cancer therapy [68]. Activation induced cytidine deaminase (AID), which is essential for both class switch recombination and somatic hypermutation, was also reported to be expressed in six breast cancer cell lines by nested RT-PCR [71].…”

Aplicação diagnóstica e terapêutica de um novo anticorpo anti-FGF2 em processos de angiogênese em melanoma experimental

“…Curiosamente, western blotting com mAb ligante de CEA 1F5H2 aponta para duas bandas, de aproximadamente 25 e 50 kDa, também identificadas por anti-FGF2 3F12E7 IgG. Por apresentarem um padrão de peso molecular característico de fragmentos correspondentes às cadeias leve e pesada de imunoglobulinas, é bastante provável que elas sejam o resultado da interação do anticorpo secundário HRPO-anti-IgG de camundongo, utilizado como parte da revelação do ensaio de western blotting, com imunoglobulinas endógenas presente na massa tumoral (Mancardi DA et al, 2013;Wang J et al, 2013), conforme observa-se na Fig. 13C.…”

“…Trabalhos na literatura relatam o papel desse fator na neovascularização de tumores (Kibbey MC et al, 1992;Miyake H et al, 1996;Wang Y et al, 1997). Ensaios in vivo com linhagens tumorais mostram uma correlação entre hiper-regulação da expressão de FGF2 e um aumento da neovascularização e potencial metastático (Miyake H et al, 1996).…”

“…Uma vez que essa associação entre FGF2 e densidade microvascular também é observada em melanomas (Wang Y et al, 1997), interferências na via de sinalização desse fator, virtualmente expresso em todos os melanomas metastáticos (al-Alousi S et al, 1996a, al-Alousi S et al, 1996b, representam uma opção de terapia antiangiogênica a ser abordada para essa enfermidade.…”