Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling.

Autor:	Matsushita M; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Fujita K; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan. kazufujita2@gmail.com.; Department of Urology, Kindai University, Faculty of Medicine, Osakasayama, Japan., Hayashi T; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Kayama H; Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan.; WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.; Institute for Advanced Co-Creation Studies, Osaka University, Suita, Japan., Motooka D; Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan., Hase H; Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan., Jingushi K; Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan., Yamamichi G; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Yumiba S; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Tomiyama E; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Koh Y; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Hayashi Y; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Nakano K; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Wang C; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Ishizuya Y; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Kato T; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Hatano K; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Kawashima A; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Ujike T; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Uemura M; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Imamura R; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan., Rodriguez Pena MDC; Department of Pathology, UAB School of Medicine, Birmingham, Alabama., Gordetsky JB; Departments of Pathology and Urology, Vanderbilt University Medical Center, Nashville, Tennessee., Netto GJ; Department of Pathology, UAB School of Medicine, Birmingham, Alabama., Tsujikawa K; Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan., Nakamura S; Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan., Takeda K; Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan.; WPI Immunology Frontier Research Center, Osaka University, Suita, Japan., Nonomura N; Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Aug 01; Vol. 81 (15), pp. 4014-4026. Date of Electronic Publication: 2021 May 26.
DOI:	10.1158/0008-5472.CAN-20-4090
Abstrakt:	Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales , inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro . Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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