Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth

Gao, Yajuan; Islam, Mohammad Shyful; Jing, Tian; Lui, Vivian Wai Yan; Xiao, Dong

doi:10.1016/j.canlet.2014.03.015

Cited by 107 publications

(78 citation statements)

References 43 publications

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“…For example, in a prostate cancer xenograft model, fatty acid synthesis genes are highly expressed in the primary tumor, suppressed following castration, and then upregulated as resistant tumors emerge, suggesting potential involvement of fatty acid metabolism in CRPC development [23]. Inhibiting lipogenic enzymes such as fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), or ACLY produces anti-cancer effects both in prostate cancer cell lines and mouse models [10, 26–30]. Activation of AMP-activated protein kinase (AMPK), which inhibits fatty acid synthesis by phosphorylating ACC [31], also inhibits prostate tumorigenesis [10, 32–35].…”

Section: Introductionmentioning

confidence: 99%

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

Shah

Carriveau

et al. 2016

Oncotarget

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The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased β-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

Shah

Carriveau

et al. 2016

Oncotarget

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“…Cucurbitacins are a group of highly oxidized tetracyclic triterpenoids, and the screening study of these on the cytotoxic activity indicated that cucurbitacins possess strong anti-cancer activity, especially cucurbitacin B, D, E, I and compound 9 [3,10,14–17]. The report pointed out that cucurbitacin-I induced G 2 /M cell cycle arrest in SW480 cells accompanied by the downregulation of cyclin A, cyclin B1, CDK1 and CDC25C in vitro and in vivo [18].…”

Section: Resultsmentioning

confidence: 99%

“…Extracted from the rhizomes, roots or the juice of various plants such as Siraitia grosvenorii (Cucurbitaceae) or Momordica Linn. (Cucurbitaceae), tetracyclic triterpenes have been reported with multiple biological activities including anti-inflammatory function, cytotoxicity and anti-cancer, preventive and curative effects against CCl 4 -induced hepatotoxicity and anti-fertility activities [1–3]. The genus Hemsleya (Cucurbitaceae) includes approximately 30 species, distributed in the subtropical to temperate regions in Asia, eastern India and northern Vietnam.…”

Section: Introductionmentioning

confidence: 99%

Identification of 16,25- O -diacetyl-cucurbitane F and 25- O -acetyl-23,24-dihydrocucurbitacin F as novel anti-cancer chemicals

et al. 2018

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Seven new cucurbitane glucosides, hemslepensides J-P (1–7), and two known compounds, 16,25-O-diacetyl-cucurbitane F (8) and 25-O-acetyl-23,24-dihydrocucurbitacin F (9), were isolated from the tubers of Hemsleya pengxianensis var. jinfushanensis. The structures of 1–7 were elucidated using infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. The treatment of HT29 cells, human colon cancer cells, with compounds 8 and 9 inhibited cell proliferation. Further study demonstrated that compounds 8 and 9 induced F-actin aggregation, G2/M phase cell cycle arrest and cell apoptosis in HT29 cells. In summary, the present study enriched the chemical composition research of H. pengxianensis, and suggested that the compounds 8/9 treatment may be a potentially useful therapeutic option for colon cancer.

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“…[12] In particular, antiproliferative activity has been found in eight cucurbitacins, including cucurbitacin B, D, E, I, IIa, L, Q, and R. [13,14] Furthermore, the anticancer properties of several variants of cucurbitacins have been observed both in vitro and in vivo. [15][16][17] Cucurbitacin promotes apoptosis in colon cancer tested by tumor models of syngeneic transplanted mice [17] and induces apoptosis in pancreatic cancer cells. [18] These mechanisms indicate that inhibition of the JAK/STAT3 pathway by cucurbitacin may be effective in cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin Attenuates Hyperglycemia by Increasing Glut2 Through Pi3k-Pakt in the Hepatocytes of Streptozotocin Induced Diabetic Rats

Banu¹

2017

WJPPS

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The current study was undertaken to investigate the role of cucurbitacin in the regulation of hepatic expression of insulin signaling proteins and the underlying mechanism. Diabetes was induced with a single dose of streptozotocin (40 mg/kg bw/i.p). Diabetic rats were treated with cucurbitacin (5 mg/kg bw) for 45 days. Diabetic rats showed significant decrease in protein expression of PI3K, p-Akt and GLUT2, and the immunohistochemistry of IR, p-Akt and GLUT2 in liver showed abnormal changes. However, the administration of cucurbitacin in diabetic rats showed to enhance IR, p-Akt and GLUT2 expressions when compared with diabetic rats. Immunostaining showed that administration of cucurbitacin in diabetic rats demonstrated a positive GLUT2 staining in pancreas and synthesis of IR, p-Akt and GLUT2 in the hepatocytes. Based on the present findings, the antidiabetic potential of cucurbitacin could improve insulin action and glucose metabolism through activation of GLUT2 protein in liver and pancreas.

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Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth

Cited by 107 publications

References 43 publications

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism

Identification of 16,25- O -diacetyl-cucurbitane F and 25- O -acetyl-23,24-dihydrocucurbitacin F as novel anti-cancer chemicals

Cucurbitacin Attenuates Hyperglycemia by Increasing Glut2 Through Pi3k-Pakt in the Hepatocytes of Streptozotocin Induced Diabetic Rats

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