Suppression of pancreatic cancer proliferation through TXNIP-mediated inhibition of the MAPK signaling pathway

Abstract

Thioredoxin-interacting protein (TXNIP) is a crucial thioredoxin-binding protein that is recognized as a tumor suppressor in diverse malignancies, such as breast cancer, lung cancer, hepatocellular carcinoma, and thyroid cancer. However, the specific role and molecular mechanisms of TXNIP in the pathogenesis and progression of pancreatic cancer cells have not been determined. In this study, we investigate the relationship between TXNIP expression and overall survival prognosis in pancreatic cancer patients. Mechanistic studies are conducted to reveal the role of TXNIP in pancreatic cancer cell proliferation, migration, and regulation during malignancy. Our findings indicate that patients with high TXNIP expression have a more favorable prognosis. In vitro experiments with pancreatic cell lines show that overexpression of TXNIP suppresses the proliferation and migration of pancreatic cancer cells. Furthermore, we find that TXNIP inhibits the activation of the MAPK signaling pathway, thereby decreasing the malignant potential of pancreatic cancer. In conclusion, our study reveals TXNIP as a promising new predictive marker and therapeutic target for pancreatic cancer.

1. Introduction

Pancreatic cancer is one of the most lethal malignancies worldwide and is characterized by aggressive tumor progression, late-stage diagnosis, and resistance to conventional therapies [1–3]. The complex interplay of genetic and epigenetic alterations contributes to the dysregulation of critical pathways involved in pancreatic carcinogenesis [4–6], emphasizing the need for novel molecular targets and therapeutic strategies [7,8].

Thioredoxin-interacting protein (TXNIP) is a member of the alpha arrestin protein family and serves as a key interlocutor within the thioredoxin (TXN) antioxidant system [9]. TXNIP plays a pivotal role in regulating the levels of reactive oxygen species (ROS) and promoting inflammatory responses, and is an important factor in intracellular oxidative stress responses [10–12]. Previous evidence has shown that TXNIP expression is characteristically down-regulated in a spectrum of cancers, including lung cancer, hepatic carcinoma, and gastric malignancies [13–15]. The tumor-suppressive attributes of TXNIP are manifested in several ways. In breast cancer, TXNIP can suppress cell proliferation via metabolic reprogramming and attenuate cell invasion and migration through the TXNIP-HIF1α-TWIST signaling pathway [16]. In bladder cancer, TXNIP can promote apoptosis by inhibiting Erk protein activation [16]. These observations suggest that suppression of TXNIP expression may facilitate the malignant transformation of tumor cells, whereas enhancement of TXNIP expression could influence the metabolic state of tumor cells, thereby inhibiting their proliferative, invasive, and other malignant potentials. However, the specific role and potential mechanisms of TXNIP in pancreatic cancer remain largely unclarified.

In this study, we investigated the role of TXNIP in pancreatic cancer. Our results highlighted the key role of TXNIP in suppressing tumor cell proliferation and mitigating metastasis. We also revealed that these anticarcinogenic properties stem from modulation of the MAPK signaling pathway, particularly through the dephosphorylation of Erk1/2. Overall, this study reveals new prognostic markers and potential therapeutic targets for pancreatic cancer.