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

Abstract

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.

Specific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression

“…A recent study showed that commensal gut microbiota contributes to hormonal resistance in castration-resistant PCa by providing an alternative source of androgens [17]. Moreover, short-chain fatty acids derived from gut microbiota of the mice fed with an HFD promote PCa growth through insulin-like growth factor (IGF) signaling [18]. The aforementioned studies support the clinical importance of interaction among diet, microbiome, and PCa development and progression.…”

A Prostate Cancer Proteomics Database for SWATH-MS Based Protein Quantification

“…MYC mRNA and protein overexpression in PCa tumour foci corresponds with disease severity [ 37 ]. IGF1, a downstream MAPK and PI3K receptor, boosts their signalling and promotes the formation of PCa [ 41 ]. The recurrence of castration-resistant PCa is influenced by androgen receptor signalling [ 42 ].…”

The Effects and Mechanisms of Flavonoids on Cancer Prevention and Therapy: Focus on Gut Microbiota

“…For instance, Clostridium could transform glucocorticoids into androgens in the gut, which facilitated the development of prostate cancer 97 . Gut microbiota-derived SCFA upregulated local and systemic insulin-like growth factor-1 (IGF-1), which favored prostate cancer development 98 . Ruminococcus , which was involved in glycerolphospholipid metabolism, promoted prostate cancer progression by upregulating lysophosphatidylcholine acyltransferase 1 (LPCAT1) and activating DNA repair pathways 99 .…”