Gut dysbiosis promotes prostate cancer progression and docetaxel resistance via activating NF-κB-IL6-STAT3 axis

Abstract

Background The gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies. However, the underlying mechanisms behind how it exerts some effect on prostate cancer, as an extra-intestinal tumor, in a contact-independent way remain elusive and deserve exploration. Antibiotic exposure, one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis, is associated with multiple disorders. This study aims to preliminarily clarify the link between gut dysbiosis and prostate cancer. Results First, we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water promoted the growth of subcutaneous and orthotopic tumors in mice. Fecal microbiota transplantation could transmit the effect of antibiotic exposure on tumor growth. Then, 16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotic exposure. Meanwhile, intratumoral lipopolysaccharide (LPS) profoundly increased under the elevation of gut permeability. Both in vivo and in vitro experiments revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated prostate cancer proliferation and docetaxel chemoresistance. Finally, 16S rRNA sequencing of patients’ fecal samples revealed that Proteobacteria was enriched in patients with metastatic prostate cancer and was positively correlated with plasma IL6 level, regional lymph node metastasis status, and distant metastasis status. The receiver operating characteristic (ROC) curves showed that the relative abundance of Proteobacteria had better performance than the prostate-specific antigen (PSA) level in predicting the probability of distant metastasis in prostate cancer (area under the ROC curve, 0.860; p < 0.001). Conclusion Collectively, this research demonstrated that gut dysbiosis, characterized by the enrichment of Proteobacteria due to antibiotic exposure, resulted in the elevation of gut permeability and intratumoral LPS, promoting the development of prostate cancer via the NF-κB-IL6-STAT3 axis in mice. Considering findings from human patients, Proteobacteria might act as an intestinal biomarker for progressive prostate cancer.

Effects of Green Tea Catechins on Prostate Cancer Chemoprevention: The Role of the Gut Microbiome

“…For example, gut microbes produce sex hormones, such as androgen, and, in a study by Pernigoni et al, multiple species among mice and humans produced androgens from androgen precursors, in turn promoting progression of castrate resistant PCa [ 107 ]. In a study of both mice and PCa patients, Proteobacteria was increased after antibiotic exposure, and was in turn associated with development of PCa in mice and with metastasis of PCa among humans [ 108 ]. In a study of mice on a high-fat diet, the resultant alterations to the mice fecal microbiome promoted histamine biosynthesis and increased inflammatory cancer cell growth [ 109 ].…”

Activation of the β‑TrCP/IκBα/inflammation axis limits the sensitivity of liver cancer cells to neddylation inhibition

“…The results of previous studies have demonstrated that inflammation could lead to chemoresistance of cancer cells (17,33). Zhong et al revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS promoted the expression of cyclin D1, c-Myc, Bcl-2 and survivin, facilitating prostate cancer proliferation and docetaxel chemoresistance (33). Neddylation-inhibitor MLN4924 exhibits broad anticancer potential and may be used as a chemotherapeutic agent in the future.…”

Effects of the intestinal microbiota on prostate cancer treatment by androgen deprivation therapy

“…Dysbiosis is often associated with an increase in gut permeability and endotoxinemia, which is an increase in the circulating level of bacterial lipopolysaccharide (LPS) [ 10 , 11 ]. In mice, dysbiosis induced by broad-spectrum antibiotics favors the accumulation of LPS in subcutaneous and orthotopic PC, thereby activating local inflammation and promoting tumor growth [ 12 ]. High fat diet-induced dysbiosis also triggers an LPS-mediated pro-inflammatory pathway secondary to the LPS-induced upregulation of the histamine-producing enzyme histidine decarboxylase (HDC) in mast cells infiltrating the tumor [ 13 ].…”

“…Such studies are urgently awaited. Of note, in PC patients, the fecal abundance of Proteobacteria correlates with the presence of distant metastases [ 12 ]. Thus, there is circumstantial evidence suggesting that intestinal dysbiosis contributes to prostate carcinogenesis and tumor progression ( Fig.…”