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| Status |
Public on Jun 10, 2017 |
| Title |
Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Prostate cancer (PCa) is the most common malignancy among western men and the second leading-cause of cancer related deaths. For men who develop metastatic, castration-resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. Deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid catabolism to fuel PCa growth. In fact, the CPT1A isoform is abundant in PCa, especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased AR content and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of this findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.
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| Overall design |
Prostate cancer LNCaP cells with two different shRNAs for CPT1A were compared to non-targetting shRNA controls.
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| Contributor(s) |
Flaig TW, Salzmann-Sullivan M, Su L, Zhang Z, Joshi M, Gijon MA, Kim J, Arcaroli JJ, van Bokhoven A, La Rosa LG, Schlaepfer IR |
| Citation |
https://doi.org/10.18632/oncotarget.17359
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| Submission date |
Jun 20, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Jihye Kim |
| E-mail(s) |
kim.jihey@gmail.com
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| Phone |
7209755448
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| Organization name |
Cleveland Clinic
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| Department |
Quantitative Health Sciences
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| Street address |
9500 Euclid Ave.
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| City |
Cleveland |
| State/province |
Ohio |
| ZIP/Postal code |
44195 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA326312 |
| SRA |
SRP076884 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE83547_Individual_FPKM_Annot.txt.gz |
995.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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