Structure-based assessment and network analysis of targeting 14-3-3 proteins in prostate cancer

Abstract

Developing combination therapy for castrate-resistant prostate cancer (CRPC) may require exploiting new drug targets outside androgen receptor and PI3K / AKT / mTOR signal transduction pathways implicated in prostate cancer (PCa) progression. One such possible new target is YWHAZ of the 14-3-3 protein family as this gene has prognostic significance for metastatic CRPC patients. However, there are no small molecules targeting YWHAZ commercially available. Hence, we explored whether the small molecule BV02 targeting another 14-3-3 protein family member SFN also binds to YWHAZ. Using advanced docking algorithms we find that BV02 docks many other 14-3-3 family members. In addition, the amphipathic groove where drug binding occurs also has a high binding affinity for other drugs used to treat PCa such as docetaxel. The proteome of metastatic PCa models (LNCaP clone FGC and PC-3) was perturbed as a result of BV02 treatment. Through data integration of three proteomics data sets we found that BV02 modulates numerous protein-protein interactions involving 14-3-3 proteins in our PCa models.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0905-y) contains supplementary material, which is available to authorized users.

<p>miR-31-5p Regulates <em>14-3-3 ɛ</em> to Inhibit Prostate Cancer 22RV1 Cell Survival and Proliferation via PI3K/AKT/Bcl-2 Signaling Pathway</p>

“…36 Previous studies have implicated 14-3-3ε as a cell enhancer factor that promotes cell proliferation in breast cancer cells, 12 gastric cancer SGC7901 cells, 37 and hepatocellular carcinoma 14 and as a potential novel genetic risk factor for HIV neurocognitive impairment, 24 major depressive disorder in males of the Chinese Han population, 38 and development of midline craniofacial structures. 39 Recently, Alex and colleagues 9 suggested that 14-3-3ε and other family members play an important role in the development and progression of PCa, indicating that it can be employed as a drug target in the treatment of PCa. In the present study, we found that 14-3-3ε is significantly upregulated in PCa cell lines and acts as a cell enhancer factor to promote PCa cell proliferation, migration, and invasion.…”

“…8 This family may be used as a novel target for the diagnosis and treatment of PCa. 9 14-3-3 Proteins are a family of conserved regulatory molecules that are expressed in eukaryotic cells. 10 14-3-3 Proteins regulate intracellular signaling pathways through the phosphorylation of serine/threonine motifs of target proteins that are related to signal transduction, protein trafficking, cell cycle, and apoptosis.…”

“…23 Li et al used proteomics to compare the protein expression of different metastatic breast cancer cell lines and found that the expression level of 14-3-3ε in lowly metastatic tumor cells was higher than that in highly metastatic cell lines. 16 Recently, Alex and colleagues 9 have suggested that 14-3-3ε and other family members play an important role in the development and progression of PCa, and thus can be potentially used as drug targets in the treatment of PCa. In addition, 14-3-3ε may serve as a novel prognostic biomarker or therapeutic target for HCC, 14 breast cancer, 12 and HIV neurocognitive impairments.…”

“…Currently, chemotherapeutic drugs that target 14-3-3ε in PCa mainly include docetaxel and a non-peptidic small-molecule inhibitor of SFN known as BV02. 9 However, due to the harmful side effects of chemotherapeutic drugs, there is an urgent need to identify safer therapies for PCa.…”

The survival analysis and oncogenic effects of CFP1 and 14-3-3 expression on gastric cancer

“…14-3-3ζ has been identified as an oncogene of several tumors, and overexpression of 14-3-3ζ was frequently detected in lung adenocarcinoma tissues, and was significantly associated with lymph node metastasis and adverse outcomes [32]. In the study of prostate cancer, the 14-3-3 family of YWHAZ, which is associated with the prognosis of metastatic prostate cancer, can be used as a target for prostate cancer treatment [33]. Related experiments in breast cancer found that phosphorylation of BAD at S118 stimulates the survival pathway, which in turn phosphorylates BAD at S99, resulting in binding to the 14-3-3 protein, thereby affecting the proliferation of breast cancer tumor cells [34].…”