Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

Akash K. Kaushik; Ali Shojaie; Katrin Panzitt; Rajni Sonavane; Harene Venghatakrishnan; Mohan Manikkam; Alexander Zaslavsky; Vasanta Putluri; Vihas T. Vasu; Yiqing Zhang; Ayesha S. Khan; Stacy Lloyd; Adam T. Szafran; Subhamoy Dasgupta; David A. Bader; Fabio Stossi; Hangwen Li; Susmita Samanta; Xuhong Cao; Efrosini Tsouko; Shixia Huang; Daniel E. Frigo; Lawrence Chan; Dean P. Edwards; Benny A. Kaipparettu; Nicholas Mitsiades; Nancy L. Weigel; Michael Mancini; Sean E. McGuire; Rohit Mehra; Michael M. Ittmann; Arul M. Chinnaiyan; Nagireddy Putluri; Ganesh S. Palapattu; George Michailidis; Arun Sreekumar

doi:10.1038/ncomms11612

Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

Akash K. Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas T. Vasu, Yiqing Zhang, Ayesha S. Khan, Stacy Lloyd, Adam T. Szafran, Subhamoy Dasgupta, David A. Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini TsoukoShixia Huang, Daniel E. Frigo, Lawrence Chan, Dean P. Edwards, Benny A. Kaipparettu, Nicholas Mitsiades, Nancy L. Weigel, Michael Mancini, Sean E. McGuire, Rohit Mehra, Michael M. Ittmann, Arul M. Chinnaiyan, Nagireddy Putluri, Ganesh S. Palapattu, George Michailidis, Arun Sreekumar

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-Acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-Acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.

Original language	English (US)
Article number	11612
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11612
State	Published - May 19 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/ncomms11612

Cite this

Kaushik, A. K., Shojaie, A., Panzitt, K., Sonavane, R., Venghatakrishnan, H., Manikkam, M., Zaslavsky, A., Putluri, V., Vasu, V. T., Zhang, Y., Khan, A. S., Lloyd, S., Szafran, A. T., Dasgupta, S., Bader, D. A., Stossi, F., Li, H., Samanta, S., Cao, X., ... Sreekumar, A. (2016). Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer. Nature communications, 7, Article 11612. https://doi.org/10.1038/ncomms11612

Kaushik, AK, Shojaie, A, Panzitt, K, Sonavane, R, Venghatakrishnan, H, Manikkam, M, Zaslavsky, A, Putluri, V, Vasu, VT, Zhang, Y, Khan, AS, Lloyd, S, Szafran, AT, Dasgupta, S, Bader, DA, Stossi, F, Li, H, Samanta, S, Cao, X, Tsouko, E, Huang, S, Frigo, DE, Chan, L, Edwards, DP, Kaipparettu, BA, Mitsiades, N, Weigel, NL, Mancini, M, McGuire, SE, Mehra, R, Ittmann, MM, Chinnaiyan, AM, Putluri, N, Palapattu, GS, Michailidis, G & Sreekumar, A 2016, 'Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer', Nature communications, vol. 7, 11612. https://doi.org/10.1038/ncomms11612

@article{e4e6fdc8d9914347aa7ed5ccbb7c515f,

title = "Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer",

abstract = "The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-Acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-Acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.",

author = "Kaushik, {Akash K.} and Ali Shojaie and Katrin Panzitt and Rajni Sonavane and Harene Venghatakrishnan and Mohan Manikkam and Alexander Zaslavsky and Vasanta Putluri and Vasu, {Vihas T.} and Yiqing Zhang and Khan, {Ayesha S.} and Stacy Lloyd and Szafran, {Adam T.} and Subhamoy Dasgupta and Bader, {David A.} and Fabio Stossi and Hangwen Li and Susmita Samanta and Xuhong Cao and Efrosini Tsouko and Shixia Huang and Frigo, {Daniel E.} and Lawrence Chan and Edwards, {Dean P.} and Kaipparettu, {Benny A.} and Nicholas Mitsiades and Weigel, {Nancy L.} and Michael Mancini and McGuire, {Sean E.} and Rohit Mehra and Ittmann, {Michael M.} and Chinnaiyan, {Arul M.} and Nagireddy Putluri and Palapattu, {Ganesh S.} and George Michailidis and Arun Sreekumar",

note = "Funding Information: NIH 1RO1CA133458-01 (A.S.K.), NIH U01 CA167234 and DOD W81XWH-12-1-0130 (A.S.K., G.S.P. and G.M.), NSF DMS-1161759 (A.S.K., G.M., A.S.)",

year = "2016",

month = may,

day = "19",

doi = "10.1038/ncomms11612",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

AU - Kaushik, Akash K.

AU - Shojaie, Ali

AU - Panzitt, Katrin

AU - Sonavane, Rajni

AU - Venghatakrishnan, Harene

AU - Manikkam, Mohan

AU - Zaslavsky, Alexander

AU - Putluri, Vasanta

AU - Vasu, Vihas T.

AU - Zhang, Yiqing

AU - Khan, Ayesha S.

AU - Lloyd, Stacy

AU - Szafran, Adam T.

AU - Dasgupta, Subhamoy

AU - Bader, David A.

AU - Stossi, Fabio

AU - Li, Hangwen

AU - Samanta, Susmita

AU - Cao, Xuhong

AU - Tsouko, Efrosini

AU - Huang, Shixia

AU - Frigo, Daniel E.

AU - Chan, Lawrence

AU - Edwards, Dean P.

AU - Kaipparettu, Benny A.

AU - Mitsiades, Nicholas

AU - Weigel, Nancy L.

AU - Mancini, Michael

AU - McGuire, Sean E.

AU - Mehra, Rohit

AU - Ittmann, Michael M.

AU - Chinnaiyan, Arul M.

AU - Putluri, Nagireddy

AU - Palapattu, Ganesh S.

AU - Michailidis, George

AU - Sreekumar, Arun

N1 - Funding Information: NIH 1RO1CA133458-01 (A.S.K.), NIH U01 CA167234 and DOD W81XWH-12-1-0130 (A.S.K., G.S.P. and G.M.), NSF DMS-1161759 (A.S.K., G.M., A.S.)

PY - 2016/5/19

Y1 - 2016/5/19

N2 - The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-Acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-Acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.

AB - The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-Acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-Acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC.

UR - http://www.scopus.com/inward/record.url?scp=84971280472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971280472&partnerID=8YFLogxK

U2 - 10.1038/ncomms11612

DO - 10.1038/ncomms11612

M3 - Article

C2 - 27194471

AN - SCOPUS:84971280472

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 11612

ER -

Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this