Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors

Abstract

Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castrationresistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten (i)peÀ/À mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castrationresistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia-inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten (i)peÀ/À mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten-deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.

Unveiling Novel Double-Negative Prostate Cancer Subtypes Through Single-Cell RNA Sequencing Analysis

“…Raw data of 6 human studies in the SRA database were used to build HuPSA, including GSE210358 6 , GSE137829 13 , GSE193337 14 , GSE206962, GSE181294 15 , GSE185344 16 . Data of 12 mouse studies were used to build MoPSA, including GSE146811 39 , GSE164969 17 , GSE201956 40 , GSE216158 18 , GSE221755 19 , GSE171336 20 , GSE165741 21 , GSE174471 22 , GSE210358 6 , GSE163316 23 , GSE189307 24 , GSE158468 25 , GSE153701 26 (sTable4). All FASTQ files were downloaded using SRA-Toolkit fasterq-dump function and aligned to human (GRCh38 from NCBI) or mouse (GRCm38 from Ensembl) genome using Alevin-fry 41 .…”

Analysis of genetic biomarkers, polymorphisms in ADME-related genes and their impact on pharmacotherapy for prostate cancer

“…It is established that ADT is a cornerstone in PCa management, both as a primary treatment and in combination with other treatments. ADT can be achieved by using a variety of approaches, such as surgical castration (the removal of the testicles) or medical castration (the use of medications that suppress testosterone production [ 63 ]. The application of ADT initially controls the growth and spread of prostate cancer, which leads to the shrinkage of tumors and the relief of symptoms, but in some cases, the cancer cells continue to grow despite low testosterone levels and lead to the development of CRPC [ 64 ].…”