DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Synergistic Action of FOXP3 and TSC1 Pathways in Prostate Cancer Progression

Posted July 9, 2019

Lizhong Wang, Ph.D., University of Alabama, Birmingham

 Lizhong Wang, Ph.D., University of Alabama, Birmingham
Dr. Lizhong Wang

Prostate cancer (PCa) is the most common type of cancer in men in the United States and more than 80% of men will develop PCa by the time they are 80 years old. In the majority of cases, prostate tumors are indolent and slow growing, although some become more aggressive and ultimately lethal. The mechanisms within prostate cells that control progression of the tumors to aggressive disease are not fully understood. Identification of these mechanisms could lead to the development of improved treatment options for aggressive PCa.

To help understand the molecular mechanism of progression from indolent to aggressive PCa, Dr. Lizhong Wang and his research team at the University of Alabama at Birmingham have demonstrated that Foxp3, previously identified as X-linked prostate tumor suppressor protein, and Tsc1, an essential protein component of the PI3K/Akt/Tsc1/2/mTOR signaling pathway, both inhibit tumor progression in PCa. Additionally, they found that deletions of TSC1 are frequently accompanied by FOXP3 defects. With support from the FY13 Idea Development Award – New Investigator, they examined potential cross-talk between these two proteins and how that leads to suppression of PCa tumor progression.

Through comprehensive analyses performed using both in vitro and clinically relevant in vivo models, Dr. Wang and his team found that TSC1 and FOXP3 act synergistically to suppress tumor progression through inhibition of two other proteins, mTOR and c-MYC, which promote the growth of tumor cells. Many candidate anti-tumor drugs, such as the mTOR inhibitor rapamycin, have not been successful in PCa clinical trials to date; it is believed that persistent activation of c-MYC may be the cause of resistance to these therapies. Dr. Wang’s group is therefore testing the anti-tumor effects of combining mTOR and c-MYC inhibitors using pre-clinical mouse models of PCa that were developed in their laboratory to see if the combination treatment will overcome the resistance to mTOR inhibitors commonly seen for PCa.

By providing better understanding of one mechanism that enables tumor progression from indolent to aggressive PCa, Dr. Wang has also provided evidence that further work to identify pharmaceutical drugs that target both mTOR and c-MYC may be a new therapeutic approach that will help make PCa cells more responsive to mTOR inhibitors, and ultimately enable clinicians to provide more effective treatment options for patients with aggressive PCa.

Dr. Wang's figure Dr. Wang's figure

Publications:

Liu R, Yi B, Wei S, et al. 2015. FOXP3-microRNA-146-NF-¿B axis and therapy for precancerous lesions in prostate. Cancer Res 75(8):1714-1724.

Etikala DM, Liu R, and Wang L. 2015. FOXP3-microRNA-146-NF-kB as oncotarget. Oncoscience 2(10):839-840.

Wu L, Yi B, Wei S, et al. 2019. Loss of Foxp3 and Tsc1 Accelerate Prostate Cancer Progression through a Synergistic Transcriptional and Post-translational Regulation of c-MYC. Cancer Res. 79(7):1413-1425.

Link:

Synergistic Action of FOXP3 and TSC1 Pathways During Tumor Progression

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Last updated Monday, July 8, 2019