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| Status |
Public on Apr 03, 2015 |
| Title |
Pathway-based integrative analysis reveals a key role for the hexosamine biosynthetic pathway in castrate resistant prostate cancer with therapeutic implications |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer
We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells
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| Overall design |
GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL
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| Contributor(s) |
Kaushik AK, Sreekumar A |
| Citation(s) |
27194471 |
| Submission date |
Apr 02, 2015 |
| Last update date |
Oct 03, 2019 |
| Contact name |
Akash Kumar Kaushik |
| E-mail(s) |
akkaushi@bcm.edu
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| Phone |
9362050781
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| Organization name |
Baylor College of Medicine
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| Department |
Molecular and Cellular Biology
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| Lab |
Sreekumar Lab 120D
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| Street address |
One Baylor Plaza
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| City |
Houston |
| State/province |
Texas |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL13667 |
[HG-U219] Affymetrix Human Genome U219 Array |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA280214 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE67537_RAW.tar |
47.4 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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