Abstract
Transforming growth factor (TGF)-β signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-β promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-β1 and TGF-β2 to investigate the role of TGF-β downregulation in cancer cell death. We found that the downregulation of TGF-β increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-β downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-β downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.
Highlights
The transforming growth factor (TGF) superfamily comprises three isoforms of multifunctional cytokines that regulate numerous cellular and biological functions, including cell proliferation, apoptosis, differentiation, and migration; embryonic patterning; stem cell maintenance; immune regulation; bone formation; and tissue remodeling and repair[1,2,3]
The results show that transforming growth factor β1 (TGF-β1) mRNA levels were suppressed by 80% at an multiplicity of infection (MOI) of 100, at which TGFβ2 mRNA levels were suppressed by 75% (Fig. 1a, b)
A high level of TGF-β1 has been detected in gastric cancer[55], and levels of TGF-β1 and TGF-β2 are markedly increased in hepatocellular carcinoma and pancreatic cancer cells[56,57]
Summary
The transforming growth factor (TGF) superfamily comprises three isoforms of multifunctional cytokines (namely, β1, β2, and β3) that regulate numerous cellular and biological functions, including cell proliferation, apoptosis, differentiation, and migration; embryonic patterning; stem cell maintenance; immune regulation; bone formation; and tissue remodeling and repair[1,2,3]. The wide variety of TGF-β functions is highly cell-type specific and context dependent[1,4]. TGF-β acts as a tumor suppressor in normal and early cancer cells by promoting apoptosis over proliferation, hindering immortalization[5]. TGF-β binds to two types of serine/threonine kinase receptors[14], type I and type II, which form heteromeric cell surface complexes that stimulate the canonical (Smad-dependent) signaling pathway[10].
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