Gut Microbiota Dysbiosis Accelerates Prostate Cancer Progression Through Increased LPCAT1 Expression and Enhanced DNA Repair Pathways

Gut microbiota dysbiosis is related to cancer development and progression. Our previous study showed that Ruminococcus was more abundant in CRPC (Castration-resistant prostate cancer) than HSPC (Hormone-sensitive prostate cancer) individuals. Here, we determined the potential mechanism of microbiota dysbiosis in prostate cancer (PCa) progression. Metagenomics was used to verify the gut microbial discrepancies between CRPC and HSPC individuals. Fecal microbiota transplantation (FMT) was performed by transferring the fecal suspension of CRPC or HSPC individuals to TRAMP mice. Afterwards, the mice’s prostate histopathology and gut microbiota composition were determined. Since Ruminococcus was demonstrated to correlate with phospholipid metabolism, we used lipidomics to examine the mice’s fecal lipid profiles. The expression of LPCAT1 the key enzyme for phospholipid remodeling in mice prostate was also examined. Meanwhile, both microbial functions prediction and LPCAT1 GSEA analysis (Gene Set Enrichment Analysis) indicated DNA repair pathways, we further determined the expressions of RAD51 and DNA-PKcs in mice prostate. The results showed that gut Ruminococcus was significantly more abundant in CRPC individuals. FMT using CRPC feces accelerated mice’s PCa progression and increased their gut Ruminococcus abundance. Majority of fecal lipids including lysophosphatidylcholine and phosphatidylcholine were upregulated in CRPC FMT treated mice, accompanied with enhanced expressions of LPCAT1, RAD51, and DNA-PKcs in mice prostate. We reported an abundant colonization of Ruminococcus in the gut of CRPC individuals and mice receiving their fecal suspensions, and revealed the promotive capability of Ruminococcus in PCa progression via upregulating LPCAT1 and DNA repair protein expressions. The bacterium and its downstream pathways may become the targets of therapies for PCa in the future.

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Gut Microbiota Dysbiosis Accelerates Prostate Cancer Progression Through Increased LPCAT1 Expression and Enhanced DNA Repair Pathways

SSRN Electronic Journal ◽

10.2139/ssrn.3782449 ◽

2021 ◽

Author(s):

Liu Yufei ◽

Yang Chen ◽

Zhang Zheyu ◽

Jiang Haowen

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Gut Microbiota ◽

Cancer Progression ◽

Prostate Cancer Progression ◽

Repair Pathways ◽

Gut Microbiota Dysbiosis

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Reply to Johann S. de Bono, Maha Hussain, and Jinyu Kang’s Letter to the Editor re: Konrad H. Stopsack. Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2020.09.024

European Urology ◽

10.1016/j.eururo.2020.12.018 ◽

2020 ◽

Author(s):

Konrad H. Stopsack

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Phase 3 ◽

Castration Resistant ◽

Letter To The Editor

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Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽

10.3390/cancers13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Roosa Kaarijärvi ◽

Heidi Kaljunen ◽

Kirsi Ketola

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Treatment Resistance ◽

Research Field ◽

Phenotypic Change ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Treatment Resistant ◽

Molecular Features ◽

Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

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Synergistic Targeting of PI3K/AKT Pathway and Androgen Receptor Axis Significantly Delays Castration-Resistant Prostate Cancer Progression In Vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-13-0032 ◽

2013 ◽

Vol 12 (11) ◽

pp. 2342-2355 ◽

Cited By ~ 75

Author(s):

Christian Thomas ◽

Francois Lamoureux ◽

Claire Crafter ◽

Barry R. Davies ◽

Eliana Beraldi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Akt Pathway ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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ASC-J9® suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L

Cancer Letters ◽

10.1016/j.canlet.2016.05.018 ◽

2016 ◽

Vol 379 (1) ◽

pp. 154-160 ◽

Cited By ~ 23

Author(s):

Ronghao Wang ◽

Wanying Lin ◽

Changyi Lin ◽

Lei Li ◽

Yin Sun ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Receptor Mutant

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Tumor hypoxia, DNA repair and prostate cancer progression: new targets and new therapies

Future Oncology ◽

10.2217/14796694.3.3.329 ◽

2007 ◽

Vol 3 (3) ◽

pp. 329-341 ◽

Cited By ~ 59

Author(s):

Norman Chan ◽

Michael Milosevic ◽

Robert G Bristow

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Cancer Progression ◽

Tumor Hypoxia ◽

Prostate Cancer Progression ◽

New Therapies ◽

New Targets

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Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

Biomedicines ◽

10.3390/biomedicines9101404 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1404

Author(s):

Hye-Jin You ◽

Byong-Chul You ◽

Jong-Kwang Kim ◽

Jae-Min Park ◽

Bo-Seul Song ◽

...

Keyword(s):

Prostate Cancer ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Patients ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Castration Resistant Prostate Cancer ◽

Normal Prostate ◽

Prostate Cancer Development ◽

Kinase A

Androgen signaling via the androgen receptor (AR) is involved in normal prostate development and prostate cancer progression. In addition to androgen binding, a variety of protein kinases, including cyclic AMP-dependent protein kinase A (PKA), can activate the AR. Although hormone deprivation, especially that of androgen, continues to be an important strategy for treating prostate cancer patients, the disease ultimately progresses to castration-resistant prostate cancer (CRPC), despite a continuous hormone-deprived environment. To date, it remains unclear which pathways in this progression are active and targetable. Here, we performed a proteomic analysis of VCaP cells stimulated with androgen or forskolin to identify proteins specific for androgen-induced and androgen-bypassing signaling, respectively. Patterns of differentially expressed proteins were quantified, and eight proteins showing significant changes in expression were identified. Functional information, including a Gene Ontology analysis, revealed that most of these proteins are involved in metabolic processes and are associated with cancer. The mRNA and protein expression of selected proteins was validated, and functional correlations of identified proteins with signaling in VCaP cells were assessed by measuring metabolites related to each enzyme. These analyses offered new clues regarding effector molecules involved in prostate cancer development, insights that are supported by the demonstration of increased expression levels of the eight identified proteins in prostate cancer patients and assessments of the progression-free interval. Taken together, our findings show that aberrant levels of eight proteins reflect molecular changes that are significantly regulated by androgen and/or PKA signaling pathways, suggesting possible molecular mechanisms of CRPC.

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