Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[18F]Fluoro-d-Glucose Uptake in Prostate Cancer Mouse Xenografts

Schlaepfer, Isabel R.; Glodé, L. Michael; Hitz, Carolyn A.; Pac, Colton T.; Boyle, Kristen E.; Maroni, Paul; Deep, Gagan; Agarwal, Rajesh; Lucia, Scott; Cramer, Scott D.; Serkova, Natalie J.; Eckel, Robert H.

doi:10.1007/s11307-014-0814-4

Cited by 58 publications

(55 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[ 18 F]FDG-PET imaging was performed as described previously (Schlaepfer et al, 2015). We performed single-position, whole-body imaging by using a Siemens Inveon microPET scanner at the University of Colorado Cancer Center Animal Imaging Shared Resources (AISR).…”

Section: Star Methodsmentioning

confidence: 99%

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

SUMMARY Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of HIF-1α mediates such metabolic reprogramming. Targeting HIF-1a or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.

show abstract

Section: Star Methodsmentioning

confidence: 99%

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Prior studies have demonstrated that while fatty acid oxidation (FAO) is conducted minimally in many cancer cells [59], it is important in prostate cancer cells [60–62]. We thus hypothesized that fatty acids rescue viability and suppress AMPK activation in the Combo-treated cells through ATP production via β-oxidation.…”

Section: Resultsmentioning

confidence: 98%

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

View full text Add to dashboard Cite

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.

show abstract

“…It has been increasingly recognized that alterations in lipid metabolism are a hallmark of cancer [22, 31] and some evidence indicates that prostate cancer is associated with an increased reliance of fatty acid as a metabolic fuel and as a precursor for phospholipid production to generate cell membranes [36, 37]. Accordingly, we aimed to define the lipid profile of human prostate cancer tissues and hypothesized that obesity would alter the lipidome, potentially identifying a signature that might be prognostic for aggressive disease.…”

Section: Discussionmentioning

confidence: 99%

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

Clark

Ascui

et al. 2016

Oncotarget

View full text Add to dashboard Cite

There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.

show abstract

Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[18F]Fluoro-d-Glucose Uptake in Prostate Cancer Mouse Xenografts

Cited by 58 publications

References 42 publications

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

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

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

Contact Info

Product

Resources

About