Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/loxPtechnology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Müllerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox genePem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry–based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress–induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. Cancer Res; 70(20); 8117–26. ©2010 AACR.

With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple pre-clinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of pre-clinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist’s strategy to combat cancer.

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15); 3709–14. ©2012 AACR.

This review evaluates recent findings on the mechanisms by which lipogenic enzymes are upregulated or activated in cancer cells, the implications of increased lipogenesis for cancer cell biology and the feasibility of exploiting this pathway and its regulators as targets for antineoplastic intervention. The list of cancer types showing increased lipogenic enzyme expression keeps growing and further evidence is accumulating that growth factor signaling and particularly activation of the phosphatidylinositol 3′-kinase/protein kinase B pathway plays a role in this process. This signaling pathway stimulates lipogenic gene transcription through activation of the lipogenic transcription factor sterol regulatory element-binding protein-1 and directly activates lipogenic enzymes such as ATP-citrate lyase, linking the upregulation of lipogenesis in cancer cells to the well known tumor-associated increase in glycolysis. Steroid hormones, overexpression of the ubiquitin-specific protease-2a and mutations in breast cancer susceptibility gene 1 may further enhance lipid synthesis. While fatty acid synthase is further established as a target for antineoplastic intervention, recent findings show that interference with acetyl-CoA carboxylase-α, ATP citrate lyase or the AMP-activated protein kinase limits cancer cell proliferation and survival. The same disturbances in signaling pathways responsible for oncogenic transformation may also contribute to the increased lipogenesis observed in tumor cells. Increased lipogenesis involves modulation of multiple lipogenic enzymes at both transcriptional and posttranscriptional level and is linked to other cancer-associated metabolic changes. Not only fatty acid synthase, but in fact all key enzymes involved in fatty acid synthesis as well as key metabolic regulators are potential targets for antineoplastic intervention.