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Prostate and Prostatic Diseases (2006) 9, 230–234 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 www.nature.com/pcan REVIEW

Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer

Y Liu Nuclear Medicine Service, Department of Radiology, New Jersey Medical School, University of Medicine & Dentistry of New Jersey, Newark, NJ, USA

Most malignancies have increased for requirement of rapid proliferation, which is the basis for tumor imaging through analog FDG (2-deoxy-2-fluoro-D-glucose) with positron emission tomography. One of significant characteristics of prostate cancer is slow glycolysis and low FDG avidity. Recent studies showed that prostate cancer is associated with changes of . Several involved in the metabolism of fatty acids have been determined to be altered in prostate cancer relative to normal prostate, which is indicative of an enhanced b-oxidation pathway in prostate cancer. Increased fatty acid utilization in prostate cancer provides both ATP and acetyl- (CoA); subsequently, increased availability of acetyl-CoA makes acceleration of citrate oxidation possible, which is an important energy source as well. Dominant rather than glycolysis has the potential to be the basis for imaging diagnosis and targeted treatment of prostate cancer. Prostate Cancer and Prostatic Diseases (2006) 9, 230–234. doi:10.1038/sj.pcan.4500879; published online 9 May 2006

Keywords: glycolysis; fatty acid metabolism; b-oxidation

Introduction cells forms the theoretic basis for cancer detection through uptake of the glucose analog, fluorine-18-labeled Metabolic changes during malignant transformation 2-deoxy-2-fluoro-D-glucose (F18-FDG) with positron have been noted for many years. Warburg1 first reported emission tomography (PET). Today, FDG-PET has been that cancer cells preferentially rely on glycolysis as a widely used for diagnosis, staging, restaging and major bioenergetic source even in the presence of monitoring therapy of various kinds of malignant and produce high levels of lactate and pyruvate. diseases. Glycolysis is a by which glucose is Glucose uptake across the plasma membrane is converted to pyruvate with the generation of 2 considered the rate-limiting step for glucose consump- of ATP per of glucose. Most non-dividing tion in cells.3 Transport of polar glucose across the normal , such as muscle, fully oxidize private nonpolar plasma membrane relies on glucose transporter formed from glycolysis to dioxide and in , known as GLUTs. The previous study showed the with production of 38 molecules of that there are increased GLUT expression in the ATP per molecule of glucose. These normal tissues membrane of the malignant cells compared to normal generally do not convert glucose to except cells, which may be a key step for subsequent tissue FDG when starved of oxygen. In contrast, tumors are accumulation.4,5 Among total 13 members of facilitative characterized by converting much of glucose into lactic GLUTs, cellular F18-FDG uptake is predominantly acid with sacrificing energy availability even in the related to expression of GLUT1.6,7 presence of oxygen. The rate at which tumors convert Prostate cancer remains a major concern of public glucose to lactic acid via glycolysis is generally correlated health. It is the most prevalent cancer in beings with their rate of proliferation and degree of aggressive- and the second leading cause of male cancer death in the ness.2 US. FDG-PET has not been very helpful in staging or Increased glucose consumption is a basic characteristic detection of recurrence of prostate cancer because of low of malignant cells and is linked to energy production glycolysis. Clinical trial showed that FDG accumulation from glycolysis. Amplified glucose usage by malignant does not correlate with increasing grade or stage of the tumor and there is a significant overlap in FDG uptake between benign prostate hyperplasia and prostate Correspondence: Dr Y Liu, H-141, Nuclear Medicine, University cancer.8,9 Recent study revealed that GLUT1 mRNA Hospital, 150 Bergen Street, Newark, NJ 07101, USA. E-mail: [email protected] and protein were only very weakly expressed in human Received 26 January 2006; revised 29 March 2006; accepted 29 March prostate cancer tissue, which is considered to account for 10 2006; published online 9 May 2006 low FDG avidity of prostate cancer. In vitro study also Fatty acid metabolism and prostate cancer Y Liu suggested that glucose may not be required for andro- would produce increasing level of palmitate,23 which 231 gen-dependent prostate cancer cells because LNCaP cells further drives fatty acid oxidation. can grow at control rates even in the presence of only (3) b-Oxidation is the most prominent oxidation 0.05 g/l glucose.11 As rapid in malig- reaction for fatty acids and occurs both in the nant tumors is associated with increased energy supply, and in the mitochondrion in higher eucaryotes. In if glucose consumption is not elevated in prostate cancer, contrast to mitochondrial b-oxidation, peroxisomal alterative metabolic approach, especially fatty acid b-oxidation does not contribute to energy production oxidation may exist dominantly to provide bioenergy directly, but is required for the initial oxidation of very for abnormal cells proliferation and growth. long chain fatty acids, branched chain fatty acids, intermediates and other fatty acid derivatives, which cannot be directly oxidized by the mitochondrion. There are two separate b-oxidation pathways in the Changes of fatty acid metabolism in peroxisome: the classical peroxisome proliferators-indu- prostate cancer cible pathway and non-inducible pathway composed of branched chain acyl-CoA oxidase (ACOX2) and/or Early observation suggested that in addition to the pristanoyl-CoA oxidase (ACOX3), D-bifunctional protein striking changes of glucose metabolism in human cancer, (DBP), and sterol carrier protein X.26,27 Recent study in there is often also an increase in free fatty acid turnover, vitro by Zha et al.28 showed that there is increased oxidation and clearance.12,13 The most recent study expression of mRNA, protein and accompanied enzy- showed that a mobilizing factor produced by the matic activity of DBP in prostate cancer. Furthermore, pancreatic tumor cells appears to be responsible for the their data suggested that ACOX3 is expressed in increase in whole body fatty acid oxidation.14 Recent significant level, which might contribute to peroxisomal studies revealed that prostate cancer is associated with branched chain fatty acid b-oxidation in human prostate changes of fatty acid metabolism. Several cancer. The study implied that increased peroxisomal involved in the metabolism of fatty acids have been branched chain fatty acid b-oxidation might provide determined to be altered in neoplastic prostate cells unique metabolic pathway for prostate transformation. relative to their normal counterparts. (4) There is some striking direct evidence of increased (1) Fatty acid metabolism represents a key process that fatty acid oxidation in prostate cancer recently. influences several diverse cellular pathways and char- a-Methylacyl-CoA racemase (AMACR) is a peroxisomal acteristics including , energy processing and mitochondrial involved in the b-oxidation of and .15,16 (FAS) is branched fatty acid. Both in the peroxisome and the considered to be a possible metabolic oncogene in mitochondrion, AMACR is required to catalyze the prostate cancer.17 Fatty acid synthase is overexpressed interconversion of the R- and S-, which is at both protein and mRNA levels in prostate cancer.18,19 necessary before oxidation can proceed. Multiple studies Its high expression has also been associated with revealed the consistent and specific overexpression of aggressive biologic behavior.18 Interestingly, the highest AMACR in prostate cancer versus normal prostate.29–32 levels of FAS expression are found in androgen-inde- Sequence variants of AMACR have been linked to pendent bone metastases.19 Although it is possible that prostate cancer risk. a-Methylacyl-CoA racemase enzy- synthesis of fatty acids is required for the biogenesis of matic activity is consistently elevated in prostate cancer cellular membranes in rapidly dividing tumor cells, the tissue specimen.32 All these are indicative of an enhanced simultaneous synthesis and breakdown of fatty acid is b-oxidative pathway in prostate cancer, which provides another explanation, which provides an energy source as ATP as an energy source. a in prostate cancer. The inhibition of FAS activity induces cell death in FAS-overexpressing cancer cell lines and prolongs survival of host animals implanted with tumor xenografts.20–22 Fatty acid metabolism and citrate (2) Loss of stearoyl-CoA desaturase (SCD) expression oxidation in prostate cancer is a frequent event in prostate cancer.23 Stearoyl-CoA desaturase encodes a key rate-limiting enzyme involved It is known that increased citrate oxidation is a in the synthesis of monounsaturated fatty acids. There significant metabolic characteristic for the bioenergy was a significant reduction or complete lack of SCD requirement in prostate cancer. The normal human transcripts and protein expression in human prostate prostate , as well as that of many other animals, cancer samples relative to benign .23 Based on has the of producing, accumulating and Ntambi’s observation, the expression of several ultimately secreting extraordinarily high levels of involved in the oxidation of was upregulated, citrate.33,34 In contrast to the high citrate levels associated whereas lipid synthesis genes were downregulated; with normal prostate tissue and benign hyperplasia, therefore, consequence of SCD deficiency is an activation prostate cancer is characterized by a low level of citrate, of lipid oxidation in addition to reduced which is a basis of magnetic resonance spectroscopy synthesis and storage.24 In the pool, loss of (MRS) for in situ detection of prostate cancer.35,36 SCD expression would be expected to increase cellular Magnetic resonance spectroscopy measures change of palmitate level.23 Further enhancement of the palmitate level of citrate in the form of /citrate for detection pool in neoplastic prostate epithelium would also result and localization of prostate cancer. from overexpression of the enzyme The early report demonstrated that the decrease in as described above.25 In prostate cancer, increased citrate levels was evident early in prostate malignancy expression of FAS and decreased expression of SCD and preceded the histopathologic identification of

Prostate Cancer and Prostatic Diseases Fatty acid metabolism and prostate cancer Y Liu

232 malignant cells.37 The recent studies showed that activity Diet and prostate cancer of mitochondrial (m)-aconitase, the first reaction before citrate oxidation, is significantly higher in prostate cancer There is existing evidence for an association between compared to normal prostate, which drives the utiliza- dietary fat consumption and prostate cancer. The recent tion of citrate as energy source.38 Based on bioenergetics meta-analysis of all 13 published case–control and cohort of prostate epithelial cell metabolism, Costello and studies demonstrated a statistically significant associa- Franklin proposed ‘bioenergetic theory of prostate tion for dietary fat and prostate cancer.40 Animal data malignancy’: the transformation of a citrate-producing also added credence to the concept of dietary fat as a sane epithelial cell to a malignant citrate-oxidating cell promoter of prostate cancer, independent of total energy would result in a more efficient energy-generating and body mass index.41,42 system. To meet the energetic requirements of malignant There are many possible associations between dietary cells, the metabolic transformation into citrate oxidation fat intake and risk of prostate cancer, the most significant must be an early event in preparation for the progression is that dietary fat may change androgen milieu.40 Hill of malignancy.39 et al.43 reported that urinary androgen levels decreased in Net citrate production requires the continuous avail- blacks and white males who reduced fatty intake. ability of oxaloacetate and acetyl-CoA for continuous Dorgen et al.44 performed a randomized crossover study citrate synthesis. Acetyl-coenzyme A is an only molecule of high- and low-fat dietary intervention in which levels consumed in citrate cycle and its continuous availability of total and free were increased when men is crucial for driving citrate oxidation. Typically, phos- consumed a higher fat diet. Additional mechanisms to phofructokinase, a key enzyme in regulation of glyco- explain an association between dietary fat and prostate lysis in cell metabolism, is inhibited by citrate, which also cancer are free radicals and proinflammatory fatty acid account for slow glycolysis in addition to low GLUTs on such as specific and prostaglan- the in prostate cancer. Because of limited dins produced by dietary fat.45 In addition, dietary fat availability of acetyl-CoA from slow glycolysis, fatty acid may impact serum -like level,46 oxidation is the only alternative source which cannot be which is considered to be associated with development dismissed (Figure 1). and progression of many malignancies. It is believed that Illustration demonstrates relationship between citrate a reduction in fat consumption would result in reduction production/oxidation and fatty acid pathway. in prostate cancer incidence.47,48

Figure 1 Citrate metabolism and fatty acid pathway. are broken down to fatty acids and . Fatty acids are oxidized to acetyl- coenzyme A (CoA), which enters the tricarboxylic acid cycle (TCA) cycle for ATP production and energy. The acetyl-CoA is supplied by glycolysis or/and fatty acid oxidation.

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