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| Status |
Public on Apr 01, 2022 |
| Title |
ATF3 is a converging node for AR signaling and fatty acid oxidation in castration-resistant prostate cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Prostate cancer (PCa) is the second most prevalent cancer and leading causes of death among men worldwide. Androgen deprivation is the first line of treatment for locally advanced and metastatic PCa. For men who develop metastatic castration-resistant PCa (mCRPC), survival is limited. Thus, there is a need to identify synergistic pathways to either prevent or re-sensitize the castration-resistant phenotype. PCa has a long natural history of development and there is a significant correlation between age, diet, metabolism and progress of PCa. We have previously reported that treating PCa cells with fatty acid oxidation inhibitors (FAOi) sensitizes them to androgen blockade. Here we set out to evaluate how the two disparate pathways: AR signaling and FAO, influence one another hoping to identify new therapeutic vulnerabilities. We used CRPC cell models (LNCaP-MDV-resistant, and LNCaP-C4-2), as well as the FAOi (etomoxir and ranolazine) and the antiandrogen enzalutamide (MDV3100). Cells were treated for 48 hours, followed by gene expression, androgen signaling and growth analysis. Both FAOi strongly suppressed the androgen response hallmark in MDV-res cells, and this was associated with a significant upregulation of the ATF3 gene. Interestingly, knockdown (KD) of ATF3 with shRNAs resulted in differential responses to FAOi in these genetically-related cells. In the MDV-resistant cells, ATF3 KD resulted in increased PSA expression with FAOi treatment. On the other hand, in the C4-2 cells, ATF3 KD resulted in decreased PSA expression with FAOi treatment. These results suggested that ATF3 is a convergent point for AR and FAO pathways and that is cell-context dependent, and its expression status could be exploited to sensitize PCa cells to MDV3100 and/or the FAOi. Cell growth and apoptosis assays confirmed that the LNCaP-derived ATF3 KD were more sensitive to MDV3100 and FAOi compared to control cells. Examination of patient databases revealed an inverse correlation between AR and ATF3, a low expression of ATF3 in advanced cancers and better disease-free survival in patients with high ATF3 expression. These data support the role for FAOi to re-sensitize CRPC to endocrine therapies. In conclusion, we have identified ATF3 as a modulator of FAO and AR signaling that has predictive value for clinical outcomes using FAOi in CRPC.
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| Overall design |
microarray of RNA isolated from control, Etomoxir, MDV3100, and Ranolazine treatments on CRPC cell model: LNCaP-MDV-resistant cells.
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| Contributor(s) |
Joshi M, Salzmann-Sullivan M, Stoykova GE, Kim J, Boyle KE, Flaig TW, Schlaepfer IR |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jan 11, 2019 |
| Last update date |
Apr 02, 2022 |
| 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) |
| GPL23126 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [transcript (gene) version] |
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| Samples (12)
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| GSM3560352 |
LN-Cap MDV3100 resistant MDV3100, 10µM 1 |
| GSM3560353 |
LN-Cap MDV3100 resistant MDV3100, 10µM 2 |
| GSM3560354 |
LN-Cap MDV3100 resistant MDV3100, 10µM 3 |
| GSM3560355 |
LN-Cap MDV3100 resistant Rano, 150µM 1 |
| GSM3560356 |
LN-Cap MDV3100 resistant Rano, 150µM 2 |
| GSM3560357 |
LN-Cap MDV3100 resistant Rano, 150µM 3 |
| GSM3560358 |
LN-Cap MDV3100 resistant Etomoxir, 100µM 1 |
| GSM3560359 |
LN-Cap MDV3100 resistant Etomoxir, 100µM 2 |
| GSM3560360 |
LN-Cap MDV3100 resistant Etomoxir, 100µM 3 |
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| Relations |
| BioProject |
PRJNA514722 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE124971_RAW.tar |
295.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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