Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

Zadra, Giorgia; Ribeiro, Caroline F.; Chetta, Paolo; Ho, Yeung; Cacciatore, Stefano; Gao, Xueliang; Syamala, Sudeepa; Bango, Clyde; Photopoulos, Cornelia; Huang, Ying; Tyekucheva, Svitlana; Bastos, Débora Campanella; Tchaicha, Jeremy H.; Lawney, Brian; Uo, Takuma; D’Anello, Laura; Csibi, Alfredo; Kalekar, Radha L.; Larimer, Benjamin M.; Ellis, Leigh; Butler, Lisa M.; Morrissey, Colm; McGovern, Karen; Palombella, Vito J.; Kutok, Jeffery L.; Mahmood, Umar; Bòsari, Silvano; Adams, Julian; Peluso, Stéphane; Dehm, Scott M.; Plymate, Stephen R.; Loda, Massimo

doi:10.1073/pnas.1808834116

Cited by 203 publications

(204 citation statements)

References 54 publications

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“…In prostate cancer, selective FASN inhibition antagonizes tumor growth through metabolic reprogramming and results in a reduced protein expression and reduced transcriptional activity of AR. Activation of the endoplasmic reticulum stress response, resulting in reduced protein synthesis, was involved in the FASN inhibition of the AR pathway [24]. In SDC, as well as prostate cancer, the expression of FASN might be associated with the expression of AR through the endoplasmic reticulum stress response.…”

Section: Discussionmentioning

confidence: 99%

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

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Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADPpositive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

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Section: Discussionmentioning

confidence: 99%

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

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“…However, a significant proportion of patients with PCa who receive these drugs eventually relapse and develop the resistance of these new agents . Several recent studies reported that targeting lipogenesis by selective lipogenic/FASN inhibitors would be able to overcome lethal metastatic CRPC progression and/or drug‐resistant PCa . Significantly, our data showed that osajin could coordinately suppress AR/PSA expression and FASN/lipogenesis in LNCaP and C4‐2 PCa cells.…”

Section: Discussionmentioning

confidence: 56%

“…50 Several recent studies reported that targeting lipogenesis by selective lipogenic/FASN inhibitors would be able to overcome lethal metastatic CRPC progression and/or drugresistant PCa. 33,46,51 Significantly, our data showed that osajin could SREBP-1 and SREBP-2 are transcriptional regulators that mainly activate expression of genes associated with lipogenesis, cholesterogenesis, and lipid/cholesterol homeostasis. 36,52 Specifically, SREBP-1 controls genes involved in lipogenesis, such as FASN.…”

Section: Osajin Induces Programmed Cell Death Through Caspase-depenmentioning

confidence: 64%

“…10,11,45 Blockades of androgen action, AR expression, or the AR signaling axis provide attractive therapies for PCa and its progression in patients. Therefore, therapeutic approaches designed for PCa treatment have been attempted targeting AR through specific silence of AR gene and its splice variant expression 35,46,47 or interruption of the interaction between AR and its cofactors as well as their downstream functions. 45,48,49 Clinically, the current used new generation anti-PCa drugs, such as enzalutamide or abiraterone, represent breakthroughs in the treatment of metastatic CRPC and have been demonstrated survival benefits.…”

Section: Osajin Induces Programmed Cell Death Through Caspase-depenmentioning

confidence: 99%

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Osajin displays potential antiprostate cancer efficacy via impairment of fatty acid synthase and androgen receptor expression

Huang

Hsieh

et al. 2019

The Prostate

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Background Currently, antiprostate cancer (PCa) drugs, including androgen deprivation therapy (ADT), are initially effective; however, most patients with PCa who receive ADT eventually progress to deadly aggressiveness. There is an urgent need to seek alternative strategies to cure this lethal disease. Activation of lipogenesis has been demonstrated to lead to PCa progression. Therefore, targeting the aberrant lipogenic activity could be developed therapeutically in PCa. The aim of this study is to investigate the molecular basis and efficacy of osajin, a bioactive prenylated isoflavonoid, in PCa. Methods PCa cells, LNCaP (androgen‐sensitive) and C4‐2 (androgen‐insensitive/castration‐resistant), were used in this study. Proliferation, migration, and invasion analyses were conducted by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) method, a wound healing assay, and the transwell method. Lipogenesis was determined by a Fatty Acid Quantification Kit and oil red O staining. Apoptosis was assessed by annexin V‐fluorescein isothiocyanate/propidium iodide staining, caspase enzymatic activity, and Western blot analyses. Results Osajin inhibited fatty acid synthase (FASN) expression, a key enzyme for lipogenesis, in PCa cells. By inhibiting FASN, osajin decreased the fatty‐acid levels and lipid accumulation. Significantly, osajin downregulated androgen receptor (AR) and prostate‐specific antigen (PSA) in PCa cells. Moreover, osajin suppressed PCa cell growth, migration, and invasion. Through activation of the caspase‐dependent pathway, osajin induced apoptosis in PCa cells. Conclusions These data provide a novel molecular basis of osajin in PCa cells, and cotargeting lipogenesis and the AR axis via impairment of FASN and AR expression by osajin could be applied as a new and promising approach for the treatment of malignant PCa.

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“…Selected genes known to be activated by the TR/RXR (n=33) axis were suppressed upon CRYM overexpression including B-cell leukemia 3 (BCL3) and fatty acid synthase (FASN). High FASN expression is a known feature of aggressive PCa and it has been proposed as an metabolic oncogene (14) (15,16).…”

Section: Crym Re-expression Changes the Transcriptome Revealing Thyromentioning

confidence: 99%

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

Aksoy

Pěnčík

Hartenbach³

et al. 2019

Preprint

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Highlights• Thyroid and androgen hormone driven pathways in prostate cancer (PCa) are antagonized by μ-Crystallin (CRYM).• [18F]fluoromethylcholine uptake and prognostic values in PCa correlate with CRYM protein levels.• Reduced CRYM expression predicts early biochemical recurrence (BCR) in PCa patients. AbstractAndrogen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRa/TRb) in target tissues. We show in this study that low CRYM expression levels in PCa patient samples are associated with early BCR and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in PET/MRI imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3 and androgen-mediated signalling. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

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Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

Cited by 203 publications

References 54 publications

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

Osajin displays potential antiprostate cancer efficacy via impairment of fatty acid synthase and androgen receptor expression

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

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