University of Houston researchers are continuing to increase our understanding of how androgens, such as testosterone, and androgen receptor signaling affect cellular metabolism and prostate cancer progression by targeting an aspect of metabolism called the pentose phosphate pathway. The initial treatment for advanced prostate cancer is androgen deprivation in order to block androgen receptor activity. However, this therapy is not curative and the disease often relapses into a more aggressive form of cancer with a poorer survival prognosis for the patient. By examining the metabolic processes that are active in the late-stage of this disease, researchers hope to identify novel targets for prostate cancer therapy that could lead to increased survivorship.

The pentose phosphate pathway is an alternative pathway to glycolysis used to break down sugars from the diet. “This pathway generates NADPH, a molecule used to create new cellular components and help combat dangerous reactive oxygen species. In addition, this process is also essential for the creation of new DNA and RNA. What this study demonstrated was that the expression of a key enzyme in this process, G6PD, is upregulated in prostate cancer in part by the androgen receptor even in the late-stages of this disease, implicating a deregulation in the pathway which is advantageous for cancer cell growth and survival”, explained Efrosini Tsouko, graduate student in the Center for Nuclear Receptors & Cell Signaling (CNRCS) and lead author of a paper recently published in the journal Oncogenesis.

Dangerous cellular reactive oxygen species (stained here in red, nuclei are stained blue) common in many cancers are regulated in part by the pentose phosphate pathway.

These findings indicate that the activation of the pentose phosphate pathway helps drive uncontrolled prostate cancer cell growth.

Tsouko plans to continue this research to expand the understanding of how additional key enzymes involved in glucose metabolism are deregulated in prostate cancer.

This research was conducted in the laboratory of Assistant Professor Daniel Frigo in the CNRCS. Previously, Frigo linked the androgen receptor to autophagy and targeted the AMPK-PGC-1α signaling cascade in prostate cancer.

The Frigo lab is one of several within the CNRCS concentrated on the role of nuclear receptors in cancer prevention and treatment. His team has long studied the androgen receptor, which regulates various signaling pathways. Frigo's ultimate goal is to unlock more effective and less harmful cancer treatment alternatives by targeting underexplored metabolic pathways.

Other members of the Frigo lab contributed to this project, along with collaborators at the University of Houston Department of Engineering Technology, Houston Methodist Research Institute and Baylor College of Medicine. This research was supported by the National Institutes of Health, Department of Defense, Cancer Prevention and Research Institute of Texas, Texas Emerging Technology Fund, and Golfers Against Cancer.

Established in 2009, UH’s Center for Nuclear Receptors and Cell Signaling (CNRCS) is a leading component of the UH Health initiative. Led by Jan-Åke Gustafsson, a National Academy of Sciences member and world-renowned expert in the field of nuclear receptors, CNRCS researchers are involved in many aspects of nuclear receptor research, all focused on understanding the roles of these receptors in health and disease. CNRCS researchers are working toward the goal of finding new treatments for an array of significant diseases including cancer, diabetes, metabolic syndrome and neurological disorders. Working from the center’s world-class labs, the researchers combine interdisciplinary research and dynamic collaboration with the Texas Medical Center and industry partners.

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