PIM1 drives lipid droplet accumulation to promote proliferation and survival in prostate cancer

Shailender S. Chauhan, Andrea L. Casillas, Andres D. Vizzerra, Hope Liou, Amber N. Clements, Caitlyn E. Flores, Christopher T. Prevost, David F. Kashatus, Ashley J. Snider, Justin M. Snider, Noel A. Warfel

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3β) via serine 9 phosphorylation. GSK3β inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress. (Figure presented.)

Original languageEnglish (US)
Pages (from-to)406-419
Number of pages14
JournalOncogene
Volume43
Issue number6
DOIs
StatePublished - Feb 2 2024

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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