Prostate Cancer Energetics and Biosynthesis.

Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.

Regulation and role of CAMKK2 in prostate cancer.

In 2011, CAMKK2, the gene encoding calcium/calmodulin-dependent kinase kinase 2 (CAMKK2), was demonstrated to be a direct target of the androgen receptor and a driver of prostate cancer progression. Results from multiple independent studies have confirmed these findings and demonstrated the potential role of CAMKK2 as a clinical biomarker and therapeutic target in advanced prostate cancer using a variety of preclinical models. Drug development efforts targeting CAMKK2 have begun accordingly. CAMKK2 regulation can vary across disease stages, which might have important implications in the use of CAMKK2 as a biomarker. Moreover, new non-cell-autonomous roles for CAMKK2 that could affect tumorigenesis, metastasis and possible comorbidities linked to disease and treatment have emerged and could present novel treatment opportunities for prostate cancer.

Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling.

Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic, and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5'-AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase 1 (ULK1), but independent of canonical mechanistic target of rapamycin (mTOR) activity. Increased CAMKK2-AMPK-ULK1 signaling correlated with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Similarly, an inhibitor of AMPK-ULK1 blocked autophagy, cell growth, and colony formation in prostate cancer cells. Collectively, our findings converge to demonstrate that AR can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Thus, this pathway may represent an alternative autophagic target in CRPC.

Communication between genomic and non-genomic signaling events coordinate steroid hormone actions.

Steroid hormones are lipophilic molecules produced in one cell that can travel great distances within the body to elicit biological effects in another cell. In the canonical pathway, steroid hormone binding to a nuclear receptor (NR), often in the cytoplasm, causes the receptor to undergo a conformational change and translocate to the nucleus, where it interacts with specific sequences of DNA to regulate transcription. In addition to the classical genomic mechanism of action, alternate mechanisms of steroid activity have emerged that involve rapid, non-genomic signaling. The distinction between these two major mechanisms of action lies in the subcellular location of the initiating steroid hormone action. Importantly, the mechanisms of action are not exclusive, in that each can affect the activity of the other. Here, we describe the different types of genomic and non-genomic steroid hormone signaling mechanisms and how they can influence one another to ultimately regulate biology. Further, we discuss the approaches being used to study the non-genomic signaling events and address important caveats to be considered when designing new experiments. Thus, this minireview can serve as an introduction to the diverse signaling mechanisms of steroid hormones and offers initial, experimental guidance to those entering the field.

Delineation of the androgen-regulated signaling pathways in prostate cancer facilitates the development of novel therapeutic approaches.

Although androgen deprivation therapy (ADT) is initially effective for the treatment of progressive prostate cancer, it inevitably fails due to the onset of diverse resistance mechanisms that restore androgen receptor (AR) signaling. Thus, AR remains a desired therapeutic target even in the relapsed stages of the disease. Given the difficulties in stopping all AR reactivation mechanisms, we propose that the identification of the driver signaling events downstream of the receptor offer viable, alternative therapeutic targets. Here, we summarize recently described, AR-regulated processes that have been demonstrated to promote prostate cancer. By highlighting these signaling events and describing some of the ongoing efforts to pharmacologically modulate these pathways, our goal is to advocate potential new therapeutic targets that would represent an alternative approach for blocking AR actions.

GLUT12 promotes prostate cancer cell growth and is regulated by androgens and CaMKK2 signaling.

Despite altered metabolism being an accepted hallmark of cancer, it is still not completely understood which signaling pathways regulate these processes. Given the central role of androgen receptor (AR) signaling in prostate cancer, we hypothesized that AR could promote prostate cancer cell growth in part through increasing glucose uptake via the expression of distinct glucose transporters. Here, we determined that AR directly increased the expression of SLC2A12, the gene that encodes the glucose transporter GLUT12. In support of these findings, gene signatures of AR activity correlated with SLC2A12 expression in multiple clinical cohorts. Functionally, GLUT12 was required for maximal androgen-mediated glucose uptake and cell growth in LNCaP and VCaP cells. Knockdown of GLUT12 also decreased the growth of C4-2, 22Rv1 and AR-negative PC-3 cells. This latter observation corresponded with a significant reduction in glucose uptake, indicating that additional signaling mechanisms could augment GLUT12 function in an AR-independent manner. Interestingly, GLUT12 trafficking to the plasma membrane was modulated by calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5'-AMP-activated protein kinase (AMPK) signaling, a pathway we previously demonstrated to be a downstream effector of AR. Inhibition of CaMKK2-AMPK signaling decreased GLUT12 translocation to the plasma membrane by inhibiting the phosphorylation of TBC1D4, a known regulator of glucose transport. Further, AR increased TBC1D4 expression. Correspondingly, expression of TBC1D4 correlated with AR activity in prostate cancer patient samples. Taken together, these data demonstrate that prostate cancer cells can increase the functional levels of GLUT12 through multiple mechanisms to promote glucose uptake and subsequent cell growth.