Transforming Growth Factor-β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation

Abstract

Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.

The Interplay Between TGF-β Signaling and Cell Metabolism

“…The redox imbalance, often arises from aberrant accumulation of ROS and is marked by oxidative stress, can promote progression of multiple diseases ( Sies et al, 2017 ). The crosstalk between redox metabolism and TGF-β signaling during cancer and fibrosis is comprehensively reviewed elsewhere ( Richter et al, 2015 ; Ramundo et al, 2021 ). Noteworthy, the enzyme NADPH oxidase 4 (NOX4) appears to play a main role in mediating TGF-β-induced ROS generation under many circumstances ( Cucoranu et al, 2005 ; Sturrock et al, 2006 ; Carmona-Cuenca et al, 2008 ; Michaeloudes et al, 2011 ; Boudreau et al, 2012 ).…”

Oncoprotein DJ-1 interacts with mTOR complexes to effect transcription factor Hif1α-dependent expression of collagen I (α2) during renal fibrosis

“…Similar to the role of oxidative stress in Parkinson’s disease, a role of reactive oxygen species in the pathogenesis of renal fibrosis has been established ( 6 , 50 , 95 , 96 ). In fact, TGFβ has been shown to increase reactive oxygen species due to increased expression of NADPH oxidases especially Nox4 that contribute to the expression of fibrotic markers ( 24 , 27 , 97 , 98 ). Along with quenching reactive oxygen species in neuronal cells in Parkinson’s disease, DJ-1 has been shown to regulate proliferation of cancer cells including breast, lung, thyroid, pancreas, and prostate among many ( 60 , 99 ).…”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…It was found that TGF-β regulates the production of reactive oxygen species (ROS) or modulates antioxidant systems and redox-sensitive transcription factors in cancer cell metabolism by increasing the redox imbalance. Moreover, increased ROS production may directly induce TGF-β expression at a nuclear level (Ramundo et al, 2021). Kumari et al (2021) also reported that oxidative stress and hypoxia lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), thus inducing ER stress (ERS), which is modulated by G protein-coupled receptors (GPCRs) via ERS sensors, to support cancer cell survival and inhibit cell death.…”