FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis

Abstract

Farnesyl diphosphate synthase (FDPS), a mevalonate pathway enzyme, is highly expressed in several cancers, including prostate cancer (PCa). To date, the mechanistic, functional, and clinical significance of FDPS in cancer remains unexplored. We evaluated the FDPS expression and its cancer-associated phenotypes using in vitro and in vivo methods in PTEN-deficient and sufficient human and mouse PCa cells and tumors. Interestingly, FDPS overexpression synergizes with PTEN deficiency in PTEN conditionally knockout mice (P < 0.05) and expressed significantly higher in human (P < 0.001) PCa tissues, cell lines, and murine tumoroids compared to respective controls. In silico analysis revealed that FDPS is associated with increasing Gleason score, PTEN functionally deficient status, and poor survival of PCa. Ectopic overexpression of FDPS promotes oncogenic phenotypes such as colony formation (P < 0.01) and proliferation (P < 0.01) through activation of AKT and ERK signaling by prenylating Rho A, Rho G, and CDC42 small GTPases. Of interest, knockdown of FDPS in PCa cells exhibits decreased colony growth and proliferation (P < 0.001) by modulating AKT and ERK pathways. Further, genetic and pharmacological inhibition of PI3K but not AKT reduced FDPS expression. Pharmacological targeting of FDPS by zoledronic acid (ZOL), which is already in clinics, exhibit reduced growth and clonogenicity of human and murine PCa cells (P < 0.01) and 3D tumoroids (P < 0.02) by disrupting AKT and ERK signaling through direct interference of small GTPases protein prenylation. Thus, FDPS plays an oncogenic role in PTEN-deficient PCa through GTPase/AKT axis. Identifying mevalonate pathway proteins could serve as a therapeutic target in PTEN dysregulated tumors.

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Acknowledgements

We thank Jessica Mercer for her editorial contribution to the paper. We also greatly appreciate the technical help of Ms. Garima Kaushik, Ms. Pranita Atri, and Ms. Kavita Mallya.

Funding

This work/authors are supported, in parts, by the grants from the United States Department of Defense Grant PC170891, National Institutes of Health (P01 CA217798, UO1 CA185148 and 1R01CA182435-01A1) and P30 GM106397.

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Correspondence to Surinder K. Batra.

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SKB is one of co-founders of Sanguine Diagnostics and Therapeutics, Inc. The remaining authors declare that they have no conflicts of interest.

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Seshacharyulu, P., Rachagani, S., Muniyan, S. et al. FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. Oncogene 38, 5265–5280 (2019). https://doi.org/10.1038/s41388-019-0791-9

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