Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation

Abstract

Hypoxia is an independent prognostic indicator of poor outcome in several malignancies. However, precise mechanism through which hypoxia promotes disease aggressiveness is still unclear. Here, we report that under hypoxia (1% O2), human prostate cancer (PCA) cells, and extracellular vesicles (EVs) released by these cells, are significantly enriched in triglycerides due to the activation of lipogenesis-related enzymes and signaling molecules. This is likely a survival response to hypoxic stress as accumulated lipids could support growth following reoxygenation. Consistent with this, significantly higher proliferation was observed in hypoxic PCA cells following reoxygenation associated with rapid use of accumulated lipids. Importantly, lipid utilization inhibition by CPT1 inhibitor etomoxir and shRNA-mediated CPT1-knockdown significantly compromised hypoxic PCA cell proliferation following reoxygenation. Furthermore, COX2 inhibitor celecoxib strongly reduced growth and invasiveness following hypoxic PCA cells reoxygenation, and inhibited invasiveness induced by hypoxic PCA EVs. This establishes a role for COX2 enzymatic products in the enhanced PCA growth and invasiveness. Importantly, concentration and loading of EVs secreted by PCA cells were significantly compromised under delipidized serum condition and by lipogenesis inhibitors (fatostatin and silibinin). Overall, present study highlights the biological significance of lipid accumulation in hypoxic PCA cells and its therapeutic relevance in PCA.

Lipid quantification by Raman microspectroscopy as a potential biomarker in prostate cancer

“…Lipids in cancer cells are the main fuel source for membrane synthesis and act as one of the major drivers in tumor cells, especially PCa, for growth and membrane synthesis [10]. Moreover, the rate of fatty acid synthesis and accumulation has been reported to accelerate in hypoxic PCa cells and tumor core as a survival response to hypoxic stress [11]. Following re-oxygenation, the accumulated lipids support growth and aggressiveness of PCa [8, 11].…”

Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

“…24 In another study, we reported that hypoxic PCA exosomes are loaded with a significantly higher amount of triglycerides, and hypoxic PCA exosomes-induced invasiveness could be inhibited by celecoxib. 23 Furthermore, this study suggested the important role of lipids in the biogenesis of exosomes under both normoxic and hypoxic conditions. 23 In a recent review, Sceneay et al summarized the role of exosomes in the preparation of pre-metastatic niches and metastasis, suggesting that exosomes secreted by hypoxic cancer cells could have systemic effects and could promote cancer metastasis.…”

“…23 Furthermore, this study suggested the important role of lipids in the biogenesis of exosomes under both normoxic and hypoxic conditions. 23 In a recent review, Sceneay et al summarized the role of exosomes in the preparation of pre-metastatic niches and metastasis, suggesting that exosomes secreted by hypoxic cancer cells could have systemic effects and could promote cancer metastasis. 19 It is also suggested that by using the advanced mass spectrometry based proteomics analysis of tumor-derived exosomes, it is possible to estimate the oxygenation status of the patient’s tumors.…”

“…46 We have also observed an increase in HIF-1α expression in hypoxic PCA cells associated with activation of several lipogenesis-related molecules and lipid accumulation. 23 Huss et al have reported that angiogenic switch in TRAMP (transgenic adenocarcinoma mouse prostate transgenic model) mice is driven in part by HIF-1α early in PCA progression. 47 We have also observed that HIF-1α expression increases with the disease progression in TRAMP mice associated with higher levels of several angiogenesis-related biomarkers (VEGF, VEGFR1, VEGFR2, and microvessel density) as well as increased metastasis to distant organs.…”

“…), metabolites, and sugars, and are considered important players in tumor microenvironment remodeling, both local and distant. 19,21,23,24 It is believed that a better molecular understanding of exosomes biogenesis in hypoxic cancer cells as well as their effect on receipt cells could offer new avenues for cancer control.…”