Epigenetics of Prostate Cancer and Novel Chemopreventive and Therapeutic Approaches

Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

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Molecular Mechanisms Related to Hormone Inhibition Resistance in Prostate Cancer

Cells ◽

10.3390/cells8010043 ◽

2019 ◽

Vol 8 (1) ◽

pp. 43 ◽

Cited By ~ 10

Author(s):

Veronica Mollica ◽

Vincenzo Di Nunno ◽

Alessia Cimadamore ◽

Antonio Lopez-Beltran ◽

Liang Cheng ◽

...

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Molecular Mechanisms ◽

High Sensitivity ◽

New Drugs ◽

Prostate Cancer Cells ◽

Therapeutic Approaches ◽

Hormone Production ◽

Development Of Resistance ◽

History Of

Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or binding to nuclear receptor have been evaluated and adopted in clinical practice. However, despite several hormonal treatments being available nowadays for the management of advanced or metastatic prostate cancer, the natural history of the disease leads inexorably to the development of resistance to hormone inhibition. Findings regarding the mechanisms that drive this process are of particular and increasing interest as these are potentially related to the identification of new targetable pathways and to the development of new drugs able to improve our patients’ clinical outcomes.

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MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer

Nutrients ◽

10.3390/nu11092096 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2096 ◽

Cited By ~ 3

Author(s):

Avinash Kumar ◽

Kshiti Dholakia ◽

Gabriela Sikorska ◽

Luis A. Martinez ◽

Anait S. Levenson

Keyword(s):

Prostate Cancer ◽

Intraepithelial Neoplasia ◽

Inhibitory Effect ◽

Tumor Aggressiveness ◽

Therapeutic Approaches ◽

Anticancer Efficacy ◽

Anticancer Effects ◽

And Migration

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

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