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

Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Sakthivel Muniyan, Jawed A. Siddiqui, Eric Cruz, Sunandini Sharma, Ramakrishnan Krishnan, Brigham J. Killips, Yuri Sheinin, Subodh M Lele, Lynette M Smith, Geoffrey A Talmon, Moorthy Palanimuthu Ponnusamy, Kaustubh Datta, Surinder Kumar Batra

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5265-5280
Number of pages16
JournalOncogene
Volume38
Issue number26
DOIs
StatePublished - Jun 27 2019

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Geranyltranstransferase
Monomeric GTP-Binding Proteins
Prostatic Neoplasms
Mevalonic Acid
zoledronic acid
Neoplasms
Protein Prenylation
Pharmacology
Phenotype
MAP Kinase Signaling System
Neoplasm Grading
GTP Phosphohydrolases
Growth
Phosphatidylinositol 3-Kinases
Knockout Mice
Computer Simulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. / Seshacharyulu, Parthasarathy; Rachagani, Satyanarayana; Muniyan, Sakthivel; Siddiqui, Jawed A.; Cruz, Eric; Sharma, Sunandini; Krishnan, Ramakrishnan; Killips, Brigham J.; Sheinin, Yuri; Lele, Subodh M; Smith, Lynette M; Talmon, Geoffrey A; Palanimuthu Ponnusamy, Moorthy; Datta, Kaustubh; Batra, Surinder Kumar.

In: Oncogene, Vol. 38, No. 26, 27.06.2019, p. 5265-5280.

Research output: Contribution to journalArticle

Seshacharyulu, Parthasarathy ; Rachagani, Satyanarayana ; Muniyan, Sakthivel ; Siddiqui, Jawed A. ; Cruz, Eric ; Sharma, Sunandini ; Krishnan, Ramakrishnan ; Killips, Brigham J. ; Sheinin, Yuri ; Lele, Subodh M ; Smith, Lynette M ; Talmon, Geoffrey A ; Palanimuthu Ponnusamy, Moorthy ; Datta, Kaustubh ; Batra, Surinder Kumar. / FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. In: Oncogene. 2019 ; Vol. 38, No. 26. pp. 5265-5280.
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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.",
author = "Parthasarathy Seshacharyulu and Satyanarayana Rachagani and Sakthivel Muniyan and Siddiqui, {Jawed A.} and Eric Cruz and Sunandini Sharma and Ramakrishnan Krishnan and Killips, {Brigham J.} and Yuri Sheinin and Lele, {Subodh M} and Smith, {Lynette M} and Talmon, {Geoffrey A} and {Palanimuthu Ponnusamy}, Moorthy and Kaustubh Datta and Batra, {Surinder Kumar}",
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T1 - FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis

AU - Seshacharyulu, Parthasarathy

AU - Rachagani, Satyanarayana

AU - Muniyan, Sakthivel

AU - Siddiqui, Jawed A.

AU - Cruz, Eric

AU - Sharma, Sunandini

AU - Krishnan, Ramakrishnan

AU - Killips, Brigham J.

AU - Sheinin, Yuri

AU - Lele, Subodh M

AU - Smith, Lynette M

AU - Talmon, Geoffrey A

AU - Palanimuthu Ponnusamy, Moorthy

AU - Datta, Kaustubh

AU - Batra, Surinder Kumar

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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.

AB - 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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