A recent study by TFRI’s cancer metabolism group suggests nuclear mTOR (a kinase) also works as a transcriptional regulator of metabolism in the proliferation of prostate cancer. Their findings underscore a shift in our understanding of the androgen receptor (AR) as the master transcriptional regulator of metabolism in prostate cancer.
Dr. Vincent Giguère (McGill University) is the corresponding author of an important Genes and Development paper (August 2017), which sheds light on how prostate cancer develops, survives, and grows. Results showed that mTOR, a regulator of cellular metabolism well-known for its activity in the cytoplasm, also works in the nucleus to directly affect the expression of metabolic genes.
Their paper suggests mTOR co-operates directly with the androgen receptor to regulate the expression of these genes. Together, the combined action of nuclear mTOR and the AR reprograms the metabolism of prostate cancer cells to favour their growth and proliferation. The team’s findings have brought a new understanding to the molecular mechanisms and the factors involved in promoting prostate cancer cell growth via alteration of their metabolism.
The team also successfully identified an mTOR-dependent gene signature which could help predict recurrence in prostate cancer patients. Prostate cancer is the third leading cause of cancer-related death in Canadian men, and one of the most common cancers for this demographic.
This knowledge will benefit the development of future combinatorial therapies against both mTOR and AR to treat prostate cancer. Currently, drugs targeting mTOR have not been an effective therapy for prostate cancer. The present paper suggests this could be because they target the cytoplasmic function of mTOR instead of the nuclear function.
Importantly, the present study covers the whole spectrum of cancer research, from basic mechanisms of gene regulation to the validation of these findings in gene expression data sets obtained from patient materials, as well as the demonstration that the activity of these factors can be targeted by drugs currently in use in the clinic.
Study: Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer
Authors: Étienne Audet-Walsh, Catherine R Dufour, Tracey Yee, Fatima Z Zouanat, Ming Yan, Georges Kalloghlian, Mathieu Vernier, Maxime Caron, Guillaume Bourque, Eleonora Scarlata, Lucie Hamel, Fadi Brimo, Armen G Aprikian, Jacques Lapointe, Simone Chevalier, and Vincent Giguère
Funding: This work was supported in part by a Terry Fox Research Institute New Frontiers Program Project Grant in oncometabolism and the molecular pathways that fuel cancer.