Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis

Abstract

Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

1. Introduction

Pancreatic cancer (PC) is characterized by its highly malignant nature, rapid progression, and poor response to treatment, primarily due to chemotherapy resistance [1]. This resistance can arise from both intrinsic factors and acquired resistance mechanisms [2]. The precise mechanisms underlying gemcitabine-induced resistance in PC remain largely unknown, although previous studies have suggested that epithelial-mesenchymal transition, aberrant gene expression, gene mutation, dysregulation of critical signaling pathways, such as the NF-κB and Akt signaling pathways, apoptosis, and the presence of stromal cells, highly resistant cells, and cancer stem cells are involved in the chemoresistance of PC [3‒6].

Recently, heat shock protein 90α (Hsp90α) has emerged as a key player in the chemoresistance of PC [7]. Elevated level of Hsp90α has been shown to increase the anti-apoptotic capacity of tumor cells and contribute to chemoresistance [7]. We revealed how Hsp90α promotes the chemoresistance of PC by inhibiting ferroptosis, the exact details of which have not yet been elucidated. Ferroptosis is a recently discovered non-apoptotic regulatory cell death mode characterized by lipid peroxidation due to excessive intracellular iron deposits and the accumulation of reactive oxygen species (ROS) [8]. It differs from apoptosis in terms of both morphology and mechanism. Apoptosis is a normal type of programmed cell death that can regulate tissue development and maintain homeostasis. The morphological features of apoptotic cells include reduced cell volume, damaged cell membranes, and chromatin condensation within the nucleus. In contrast, ferroptosis is characterized by mitochondrial atrophy, increased mitochondrial membrane density and thickness, decreased mitochondrial membrane cristae, and normal nuclear size with no chromatin concentration [9]. Glutathione peroxidase 4 (GPX4) plays a crucial role in eliminating detrimental lipid peroxides and preventing intracellular ferroptosis, thereby maintaining normal cellular function.

Although previous studies have linked ferroptosis to tumor resistance [9‒11], the specific mechanisms involved in the chemoresistance of PC remain poorly understood. In the present study, we revealed that Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), resulting in nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus, thereby regulating GPX4 expression [12]. Through this mechanism, Hsp90α inhibits ferroptosis and induces chemotherapy resistance in PC.