Abstract
The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.
Highlights
Prostate cancer is the second leading cause of cancer-related death in men
To determine whether tumor growth and survival within bone is associated with changes in metabolism in patients with prostate cancer, in silico analysis was performed with transcriptome data from prostate cancer bone metastases as compared to primary prostate tumors using the Kumar et al 2016 dataset of laser-capture micro dissected samples taken at rapid autopsy [10]
Using a metabolism- specific gene set analysis, six metabolic pathways were found to be significantly up-regulated in prostate cancer bone metastasis, as compared to primary prostate cancer, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) detoxification, and glutathione metabolism (Table 2)
Summary
While overall 5-year survival rates for prostate cancer are 97.8%, in metastatic disease this falls to only 30% [1]. The mainstay of treatment for metastatic prostate cancer since the 1940s has been androgen deprivation therapy (ADT), but the cancer typically becomes resistant with a median survival of approximately 3 years [2]. Docetaxel is generally considered the first-line chemotherapy for metastatic prostate cancer; only approximately 50% of patients respond, and most eventually develop resistance [4]. Prostate cancer commonly metastasizes to the bone, with skeletal involvement present in approximately 90% of patients with metastatic disease [5]. The exact reasons for this affinity remain poorly understood; once prostate cancer has colonized the bone, a vicious cycle develops where cancer cells secrete factors that dysregulate bone remodeling, leading to the release of growth factors from bone that further promote prostate cancer growth and survival. Bone remodeling is a highly energy-consuming process; the metabolic changes that underpin malignant bone disease have not been well characterized
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