NCOA6 knockdown enhances RSL3-induced ferroptosis in pancreatic cancer cells and increases the sensitivity to gemcitabine

Abstract

Ferroptosis is a type of programmed death characterized by iron-dependent lipid peroxidation, and targeting ferroptosis has been shown to efficiently kill highly aggressive cancer cells. Previously, we confirmed that nuclear receptors regulate ferroptosis in pancreatic cancer. However, whether nuclear receptor co-activators regulate ferroptosis is unclear. Here, we show that knocking down the nuclear receptor co-activator, NCOA6, enhances the sensitivity of pancreatic cancer cells to ferroptosis. Mechanistically, NCOA6 knockdown promotes the expression of ACSL4 while inhibiting the expression of SCD1, resulting in changes in lipid metabolism, sensitivity to RSL3-induced ferroptosis, and sensitivity to gemcitabine in pancreatic cancer. The relationships between NCOA6 and ACSL4 or SCD1 are further explored in clinical specimens. This study reveals that targeting NCOA6 might alleviate gemcitabine resistance in pancreatic cancer.

1. Introduction

Pancreatic cancer is a malignant tumor that seriously threatens human health. The overall 5-year survival rate is only approximately 6%. At present, the main treatment method for cancer is still surgery-based comprehensive treatment, but the surgical resection rate of this disease is low, the effect is poor, and chemotherapy is the main method of systemic treatment. Gemcitabine is a commonly used chemotherapeutic drug for pancreatic cancer that can induce the apoptosis of pancreatic cancer cells [1]. However, the resistance of pancreatic cancer to gemcitabine still affects the effectiveness of chemotherapy, which is an urgent problem [2].

Ferroptosis is a programmed death mode different from cell apoptosis, with the core event being the production of reactive oxygen species (ROS) and subsequent lipid peroxidation mediated by hydroxyl radicals (-OH), leading to membrane damage. Ferroptosis is regulated by multiple signaling or metabolic pathways. Erastin and RSL3 are ferroptosis inducers that selectively kill cancer cells with RAS mutations [3,4]. However, KRAS gene mutations are common in pancreatic cancer; therefore, pancreatic cancer is likely to be potentially sensitive to ferroptosis. The study of the relationship between pancreatic cancer and ferroptosis may have potential value for the treatment of pancreatic cancer.

NCOA6 is a nuclear receptor coactivator that participates in cellular transcription, survival, growth, and development [5,6]. It is also a gene that promotes anti-apoptosis and survival. This gene is highly expressed in various cancers, including breast cancer, lung cancer, pancreatic cancer, melanoma, colorectal cancer, and other tumors [5,7–11]. Overexpression of the NCOA6 gene is associated with poor prognosis in multiple malignancies, and studies have shown that it can promote cell invasion and migration by activating NF-κB [12]. For example, in hepatocellular carcinoma (HCC), its knockdown can disrupt cell proliferation, migration, and invasion [13]. At present, few reports exist on the role of this gene in ferroptosis. However, as an important transcription factor involved in various biological behaviors of cells, its regulatory role is extensive, and the process of ferroptosis is regulated by multiple pathways. Therefore, we believe that it is highly likely to participate in the process of ferroptosis.