EGFR/FOXO3A/LXR-α Axis Promotes Prostate Cancer Proliferation and Metastasis and Dual-Targeting LXR-α/EGFR Shows Synthetic Lethality

Abstract

Prostate cancer is the second leading cause of cancer-related death in men. Early prostate cancer has a high 5-year survival rate. However, the five-year survival rate is low in progressive prostate cancer, which manifests as bone metastasis. The EGF receptor overexpression increases during disease progression and in the development of castration-resistant disease, and may be a potential therapeutic target. Liver X receptors (LXRs) are ligand-dependent nuclear receptor transcription factors and consist of two subtypes, LXR-α and LXR-β, which can inhibit tumor growth in various cancer cells. We revealed that LXR-α, but not LXR-β, was reduced in prostate cancer tissues compared with adjacent normal tissues. LXRs' agonist GW3965 enhanced the inhibitory action of LXR-α on the proliferation and metastasis of prostate cancer cells. Furthermore, our results support the notion that LXR-α is regulated by the EGFR/AKT/FOXO3A pathway. As an EGFR inhibitor, Afatinib could weaken AKT activation and increase the expression level of FOXO3A in prostate cancer. In addition, we indicated that the combination of Afatinib and GW3965 simultaneously increased and activated LXR-α, which led to an increase of tumor suppressors, and eventually inhibited tumor progression. Therefore, the combination of EGFR inhibitor and LXRs agonist may become a potential treatment strategy for prostate cancer, especially metastatic prostate cancer.

CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer

“…4C ), representing a set of SE-driven genes addicted to transcription mediated by CDK12. Among them, numerous genes have been considered potential oncogenes in PCa (EGFR, DDR2, and RLN2) [ 38 – 40 ]. While we identified eight more genes with low mRNA levels that were associated with superior DFS in patients with PCa (Fig.…”

Cytoplasmic LXR expression is an independent marker of poor prognosis for patients with early stage primary breast cancer

“…In various LXR-positive human BC cell lines, LXR agonists inhibited cell proliferation and increased p53 protein level (Vedin et al 2009). Moreover, LXR expression was reduced in liver and prostate cancers as compared to the adjacent normal tissues, indicating that LXR expression decreases during carcinogenesis (Chen et al 2020;Long et al 2018). However, little is known about LXR expression and its prognostic value in breast cancer.…”

NEDD4L-induced ubiquitination mediating UBE2T degradation inhibits progression of lung adenocarcinoma via PI3K-AKT signaling

“…Briefly, the transfected H1299 and H358 cells were seeded into 60-mm dishes (Corning, NY, USA) in triplicate at a density of 2000 cells/well, followed by incubation at 37 °C for 14 days. The colonies were fixed with 4% paraformaldehyde for 15 min, stained with crystal violet at room temperature for 30 min, and then counted [ 30 ].…”