Prostate cancer chemoprevention by sulforaphane in a preclinical mouse model is associated with inhibition of fatty acid metabolism

Singh, Krishna B.; Kim, Su‐Hyeong; Hahm, Eun‐Ryeong; Pore, Subrata K.; Jacobs, Bruce L.; Singh, Shivendra V.

doi:10.1093/carcin/bgy051

Cited by 47 publications

(40 citation statements)

References 45 publications

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“…The detection of SFN and AITCs excreted in urine and faecal matter following consumption of cooked cruciferous vegetables where the endogenous myrosinase is inactivated in the initial cooking stages, indicates that the gut microbiota are another source of myrosinase activity. Therefore, therapeutic doses of SFN and AITCs are likely achievable to target tumour cells in the colon [104,210,211], prostate [91,95,[171][172][173] and bladder [162,[188][189][190][191][192][193]. Dietary glucosinolates are also effective in the treatment of gastric H.Pylori infections and gastric cancer.…”

Section: Cancer and Dietary Sfn And Aitc Levelsmentioning

confidence: 99%

The Glucosinolates: A Sulphur Glucoside Family of Mustard Anti-Tumour and Antimicrobial Phytochemicals of Potential Therapeutic Application

Melrose

2019

Biomedicines

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This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their anti-tumour and antimicrobial properties. Sinigrin and glucoraphanin are converted by the β-sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate (AITC) and sulphoraphanin (SFN) which constitute part of a sophisticated defence system plants developed over several hundred million years of evolution to protect them from parasitic attack from aphids, ticks, bacteria or nematodes. Delivery of these components from consumption of cruciferous vegetables rich in the glucosinolates also delivers many other members of the glucosinolate family so the dietary AITCs and SFN do not act in isolation. In vitro experiments with purified AITC and SFN have demonstrated their therapeutic utility as antimicrobials against a range of clinically important bacteria and fungi. AITC and SFN are as potent as Vancomycin in the treatment of bacteria listed by the World Health Organisation as antibiotic-resistant “priority pathogens” and also act as anti-cancer agents through the induction of phase II antioxidant enzymes which inactivate potential carcinogens. Glucosinolates may be useful in the treatment of biofilms formed on medical implants and catheters by problematic pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus and are potent antimicrobials against a range of clinically important bacteria and fungi. The glucosinolates have also been applied in the prevention of bacterial and fungal spoilage of food products in advanced atmospheric packaging technology which improves the shelf-life of these products.

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Section: Cancer and Dietary Sfn And Aitc Levelsmentioning

confidence: 99%

The Glucosinolates: A Sulphur Glucoside Family of Mustard Anti-Tumour and Antimicrobial Phytochemicals of Potential Therapeutic Application

Melrose

2019

Biomedicines

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“…To explain why the AZ + SFN combination would be most effective as a therapeutic regimen we offer the following. Recent studies support SFN as a potent antitumor agent against multiple signaling pathways in diverse cancers and targeting of mitochondrial functions where normal cells are protected [45][46][47][48][49][50]. Expression of carbonic anhydrase IX (CAIX) is highly relevant to rapidly growing and aggressive tumor cells adapting to the acidic microenvironment in rapidly growing tumors in order to maintain a more intracellular physiological pH, and thus inhibitors of CAIX can potently inhibit tumor cell viability [51,52].…”

Section: Discussionmentioning

confidence: 99%

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

et al. 2019

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Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

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“…SPOP acts as a unique tumor suppressor by, at least in part, reducing FASN expression and consequently FA synthesis and lipid metabolism in PCa cells. Since the de novo lipogenesis pathway is a potential therapeutic target for treating PCa, elucidating how FASN expression and tumor growth are regulated by SPOP may help develop new strategies for PCa treatment.…”

Section: Discussionmentioning

confidence: 99%

Speckle‐type POZ protein suppresses lipid accumulation and prostate cancer growth by stabilizing fatty acid synthase

et al. 2019

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Fatty acid synthase (FASN) is vital for maintaining lipid homeostasis in prostate cancer (PCa) cells, which have an increased rate of de novo fatty acid (FA) synthesis.Mutations in the gene encoding the tumor suppressor speckle-type POZ protein (SPOP), which is a E3 ubiquitin ligase, are a critical feature of PCa. Here, we provide evidence that FASN is a substrate of SPOP and that interaction of these proteins induces FASN ubiquitination and proteasome-dependent degradation. We showed that SPOP mutants commonly found in PCa cannot bind to FASN. Moreover, a decrease in SPOP levels upregulated FASN expression and triggered lipid accumulation in PCa cells. These results demonstrate that FASN is a crucial mediator of SPOPinduced inhibition of PCa cell growth. Our data provide evidence that SPOP regulates lipid metabolism by decreasing FASN expression and FA synthesis, resulting in tumor suppression. Taken together, our study indicates that this pathway may be a new therapeutic target for treating PCa. K E Y W O R D S fatty acid synthase, lipid metabolism, mutation, prostate cancer, speckle-type POZ protein The Prostate. 2019;79:864-871. wileyonlinelibrary.com/journal/pros 864 | Abbreviations: AR, androgen receptor; BTB, bric-a-brac tramtrack broad complex; ERG, ETS-related gene; FA, fatty acid; FASN, fatty acid synthase; FBS, fetal bovine serum; PCa, prostate cancer; PIN, prostate intraepithelial neoplasia; SPOP, speckle-type POZ protein. Gang and Xuan have contributed equally to this work.

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Prostate cancer chemoprevention by sulforaphane in a preclinical mouse model is associated with inhibition of fatty acid metabolism

Cited by 47 publications

References 45 publications

The Glucosinolates: A Sulphur Glucoside Family of Mustard Anti-Tumour and Antimicrobial Phytochemicals of Potential Therapeutic Application

The Glucosinolates: A Sulphur Glucoside Family of Mustard Anti-Tumour and Antimicrobial Phytochemicals of Potential Therapeutic Application

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

Speckle‐type POZ protein suppresses lipid accumulation and prostate cancer growth by stabilizing fatty acid synthase

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