FABP5 can substitute for androgen receptor in malignant progression of prostate cancer cells

Naeem,Abdulghani A.; Abdulsamad,Saud A.; Zeng,Hao; He,Gang; Jin,Xi; Zhang,Jiacheng; Alenezi,Bandar T.; Ma,Hongwen; Rudland,Philip S.; Ke,Youqiang

doi:10.3892/ijo.2023.5606

FABP5 can substitute for androgen receptor in malignant progression of prostate cancer cells

Authors:
- Abdulghani A. Naeem
- Saud A. Abdulsamad
- Hao Zeng
- Gang He
- Xi Jin
- Jiacheng Zhang
- Bandar T. Alenezi
- Hongwen Ma
- Philip S. Rudland
- Youqiang Ke
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Affiliations: Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool L69 3PX, UK, Department of Biochemistry and Systems Biology, Liverpool University, Liverpool L69 3PX, UK
Published online on: December 21, 2023 https://doi.org/10.3892/ijo.2023.5606
Article Number: 18
Copyright: © Naeem et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fatty acid‑binding protein 5 (FABP5) and androgen receptor (AR) are critical promoters of prostate cancer. In the present study, the effects of knocking out the FABP5 or AR genes on malignant characteristics of prostate cancer cells were investigated, and changes in the expression of certain key proteins in the FABP5 (or AR)‑peroxisome proliferator activated receptor‑γ (PPARγ)‑vascular endothelial growth factor (VEGF) signaling pathway were monitored. The results obtained showed that FABP5‑ or AR‑knockout (KO) led to a marked suppression of the malignant characteristics of the cells, in part, through disrupting this signaling pathway. Moreover, FABP5 and AR are able to interact with each other to regulate this pathway, with FABP5 controlling the dominant AR splicing variant 7 (ARV7), and AR, in return, regulates the expression of FABP5. Comparisons of the RNA profiles revealed the existence of numerous differentially expressed genes (DEGs) comparing between the parental and the FABP5‑ or AR‑KO cells. The six most abundant changes in DEGs were found to be attributable to the transition from androgen‑responsive to androgen‑unresponsive, castration‑resistant prostate cancer (CRPC) cells. These findings have provided novel insights into the complex molecular pathogenesis of CRPC cells, and have demonstrated that interactions between FABP5 and AR contribute to the transition of prostate cancer cells to an androgen‑independent state. Moreover, gene enrichment analysis revealed that the most highly enriched biological processes associated with the DEGs included those responsive to fatty acids, cholesterol and sterol biosynthesis, as well as to lipid and fatty acid transportation. Since these pathways regulated by FABP5 or AR may be crucial in terms of transducing signals for cancer cell progression, targeting FABP5, AR and their associated pathways, rather than AR alone, may provide a new avenue for the development of therapeutic strategies geared towards suppressing the malignant progression to CRPC cells.

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1	De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, Trama A, Visser O, Brenner H, Ardanaz E, et al: Cancer survival in Europe 1999-2007 by country and age: Results of EUROCARE-5-a population-based study. Lancet Oncol. 15:23–34. 2014.
2	Ferlay J, Parkin DM and Steliarova-Foucher E: Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 46:765–781. 2010.
3	Huggins C, Stevens RE Jr and Hodges CV: Studies on prostatic cancer: II. the effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 43:209–223. 1941.
4	Sharifi N, Gulley JL and Dahut WL: Androgen deprivation therapy for prostate cancer. JAMA. 294:238–244. 2005.
5	Huggins C and Hodges CV: Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 168:9–12. 2002.
6	Attar RM, Takimoto CH and Gottardis MM: Castration-resistant prostate cancer: Locking up the molecular escape routes. Clin Cancer Res. 15:3251–3255. 2009.
7	Furuhashi M and Hotamisligil GS: Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 7:489–503. 2008.
8	Haunerland NH and Spener F: Fatty acid-binding proteins-insights from genetic manipulations. Prog Lipid Res. 43:328–349. 2004.
9	Jing C, Beesley C, Foster CS, Chen H, Rudland PS, West DC, Fujii H, Smith PH and Ke Y: Human cutaneous fatty acid-binding protein induces metastasis by up-regulating the expression of vascular endothelial growth factor gene in rat Rama 37 model cells. Cancer Res. 61:4357–4364. 2001.
10	Jing C, Beesley C, Foster CS, Rudland PS, Fujii H, Ono T, Chen H, Smith PH and Ke Y: Identification of the messenger RNA for human cutaneous fatty acid-binding protein as a metastasis inducer. Cancer Res. 60:2390–2398. 2000.
11	Adamson J, Morgan EA, Beesley C, Mei Y, Foster CS, Fujii H, Rudland PS, Smith PH and Ke Y: High-level expression of cutaneous fatty acid-binding protein in prostatic carcinomas and its effect on tumorigenicity. Oncogene. 22:2739–2749. 2003.
12	Morgan EA, Forootan SS, Adamson J, Foster CS, Fujii H, Igarashi M, Beesley C, Smith PH and Ke Y: Expression of cutaneous fatty acid-binding protein (C-FABP) in prostate cancer: Potential prognostic marker and target for tumourigenicity-suppression. Int J Oncol. 32:767–775. 2008.
13	Al-Jameel W, Gou X, Forootan SS, Al Fayi MS, Rudland PS, Forootan FS, Zhang J, Cornford PA, Hussain SA and Ke Y: Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5. Oncotarget. 8:31041–31056. 2017.
14	Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I and Deutsch DG: Targeting fatty acid binding protein (FABP) anandamide transporters-a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One. 7:e509682012.
15	Lehmann F, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Lundbäck T, Rondahl L and Barf T: Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg Med Chem Lett. 14:4445–4448. 2004.
16	Kaczocha M, Rebecchi MJ, Ralph BP, Teng YH, Berger WT, Galbavy W, Elmes MW, Glaser ST, Wang L, Rizzo RC, et al: Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. PLoS One. 9:e942002014.
17	Thanos PK, Clavin BH, Hamilton J, O'Rourke JR, Maher T, Koumas C, Miao E, Lankop J, Elhage A, Haj-Dahmane S, et al: Examination of the addictive and behavioral properties of fatty acid-binding protein inhibitor SBFI26. Front Psychiatry. 7:542016.
18	Myers JS, von Lersner AK and Sang QX: Proteomic upregulation of fatty acid synthase and fatty acid binding protein 5 and identification of cancer- and race-specific pathway associations in human prostate cancer tissues. J Cancer. 7:1452–1464. 2016.
19	Kawaguchi K, Kinameri A, Suzuki S, Senga S, Ke Y and Fujii H: The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis. Biochem J. 473:449–461. 2016.
20	Zhang J, He G, Jin X, Alenezi BT, Naeem AA, Abdulsamad SA and Ke Y: Molecular mechanisms on how FABP5 inhibitors promote apoptosis-induction sensitivity of prostate cancer cells. Cell Biol Int. 47:929–942. 2023.
21	Forootan FS, Forootan SS, Gou X, Yang J, Liu B, Chen D, Al Fayi MS, Al-Jameel W, Rudland PS, Hussain SA and Ke Y: Fatty acid activated PPARγ promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter. Oncotarget. 7:9322–9339. 2016.
22	Forootan FS, Forootan SS, Malki MI, Chen D, Li G, Lin K, Rudland PS, Foster CS and Ke Y: The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer. Int J Oncol. 44:265–275. 2014.
23	Bao Z, Malki MI, Forootan SS, Adamson J, Forootan FS, Chen D, Foster CS, Rudland PS and Ke Y: A novel cutaneous fatty acid-binding protein-related signaling pathway leading to malignant progression in prostate cancer cells. Genes Cancer. 4:297–314. 2013.
24	Berthon P, Cussenot O, Hopwood L, Leduc A and Maitland N: Functional expression of sv40 in normal human prostatic epithelial and fibroblastic cells-differentiation pattern of nontumorigenic cell-lines. Int J Oncol. 6:333–343. 1995.
25	Cussenot O, Berthon P, Berger R, Mowszowicz I, Faille A, Hojman F, Teillac P, Le Duc A and Calvo F: Immortalization of human adult normal prostatic epithelial cells by liposomes containing large T-SV40 gene. J Urol. 146:881–886. 1991.
26	Cussenot O, Berthon P, Cochand-Priollet B, Maitland NJ and Le Duc A: Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections. Exp Cell Res. 214:83–92. 1994.
27	Sramkoski RM, Pretlow TG II, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D and Jacobberger JW: A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 35:403–409. 1999.
28	Stone KR, Mickey DD, Wunderli H, Mickey GH and Paulson DF: Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer. 21:274–281. 1978.
29	Kozlowski JM, Fidler IJ, Campbell D, Xu ZL, Kaighn ME and Hart IR: Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res. 44:3522–3529. 1984.
30	Leszczyński P, Śmiech M, Salam Teeli A, Haque E, Viger R, Ogawa H, Pierzchała M and Taniguchi H: Deletion of the Prdm3 gene causes a neuronal differentiation deficiency in P19 Cells. Int J Mol Sci. 21:71922020.
31	Doudna JA and Charpentier E: Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 346:12580962014.
32	Unniyampurath U, Pilankatta R and Krishnan MN: RNA interference in the age of CRISPR: Will CRISPR interfere with RNAi? Int J Mol Sci. 17:2912016.
33	Tyumentseva MA, Tyumentsev AI and Akimkin VG: Protocol for assessment of the efficiency of CRISPR/Cas RNP delivery to different types of target cells. PLoS One. 16:e02598122021.
34	Xu X, Wan T, Xin H, Li D, Pan H, Wu J and Ping Y: Delivery of CRISPR/Cas9 for therapeutic genome editing. J Gene Med. 21:e31072019.
35	Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM and McEwan RN: A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 47:3239–3245. 1987.
36	Fisher PR, Merkl R and Gerisch G: Quantitative analysis of cell motility and chemotaxis in Dictyostelium discoideum by using an image processing system and a novel chemotaxis chamber providing stationary chemical gradients. J Cell Biol. 108:973–984. 1989.
37	Graham FL and van der Eb AJ: Transformation of rat cells by DNA of human adenovirus 5. Virology. 54:536–539. 1973.
38	Reitman S and Frankel S: A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 28:56–63. 1957.
39	Al Fayi MS, Gou X, Forootan SS, Al-Jameel W, Bao Z, Rudland PR, Cornford PA, Hussain SA and Ke Y: The increased expression of fatty acid-binding protein 9 in prostate cancer and its prognostic significance. Oncotarget. 7:82783–82797. 2016.
40	Wadosky KM and Koochekpour S: Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget. 8:18550–18576. 2017.
41	Antonarakis ES, Nakazawa M and Luo J: Resistance to androgen-pathway drugs in prostate cancer. N Engl J Med. 371:22342014.
42	Al-Jameel W, Gou X, Jin X, Zhang J, Wei Q, Ai J, Li H, Al-Bayati A, Platt-Higgins A, Pettitt A, et al: Inactivated FABP5 suppresses malignant progression of prostate cancer cells by inhibiting the activation of nuclear fatty acid receptor PPARγ. Genes Cancer. 10:80–96. 2019.
43	Lanningham-Foster L, Green CL, Langkamp-Henken B, Davis BA, Nguyen KT, Bender BS and Cousins RJ: Overexpression of CRIP in transgenic mice alters cytokine patterns and the immune response. Am J Physiol Endocrinol Metab. 282:E1197–E1203. 2002.
44	Mitchell JA, Shynlova O, Langille BL and Lye SJ: Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells. Am J Physiol Endocrinol Metab. 287:E439–E445. 2004.
45	Papa M, Boscia F, Canitano A, Castaldo P, Sellitti S, Annunziato L and Taglialatela M: Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. J Comp Neurol. 466:119–135. 2003.
46	Howe BM, Bruno SB, Higgs KA, Stigers RL and Cunningham JT: FosB expression in the central nervous system following isotonic volume expansion in unanesthetized rats. Exp Neurol. 187:190–198. 2004.
47	Shin SH, Kim I, Lee JE, Lee M and Park JW: Loss of EGR3 is an independent risk factor for metastatic progression in prostate cancer. Oncogene. 39:5839–5854. 2020.
48	Christoforou P, Christopoulos PF and Koutsilieris M: The role of estrogen receptor β in prostate cancer. Mol Med. 20:427–434. 2014.
49	Mansi R, Fleischmann A, Macke HR and Reubi JC: Targeting GRPR in urological cancers-from basic research to clinical application. Nat Rev Urol. 10:235–244. 2013.
50	Meshulam T, Simard JR, Wharton J, Hamilton JA and Pilch PF: Role of caveolin-1 and cholesterol in transmembrane fatty acid movement. Biochemistry. 45:2882–2893. 2006.
51	Trigatti BL, Anderson RG and Gerber GE: Identification of caveolin-1 as a fatty acid binding protein. Biochem Biophys Res Commun. 255:34–39. 1999.
52	Edwards PA, Kast HR and Anisfeld AM: BAREing it all: The adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res. 43:2–12. 2002.
53	Nath A and Chan C: Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Sci Rep. 6:186692016.