title: 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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Schlaepfer
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.|Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Dhanya K
authors.initials: DK
authors.lastname: Nambiar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.|Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India.
authors.forename: Anand
authors.initials: A
authors.lastname: Ramteke
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Deepanshi
authors.initials: D
authors.lastname: Dhar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Bergman
authors.affiliation: Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Graner
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Maroni
authors.affiliation: Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D014280:Triglycerides; D010100:Oxygen
keywords: extracellular vesicle; hypoxia; lipids; prostate cancer; β-oxidation