Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer

Simone, Brittany A.; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Steven; Wright, Christopher M.; Savage, Jason E.; Gitman, Robert; Lim, Mi Jung; Palazzo, Juan; Mehta, Minesh P.; Simone, Nicole L.

doi:10.1080/15384101.2016.1160982

Cited by 50 publications

(35 citation statements)

References 39 publications

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“…Moreover, our general finding of VEGFA sensitivity to starvation and subsequent accumulation with autophagic inhibitors transcends proteoglycan-driven endothelial cell autophagy. Starvation-evoked VEGFA clearance may augment the clinical benefits of caloric restriction as a potent modality to curb breast tumorigenesis by enhancing immunotherapies (105), radiation efficacy (106), and alleviating the metastatic burden (107,108).…”

Section: Discussionmentioning

confidence: 99%

Catabolic degradation of endothelial VEGFA via autophagy

Neill

Chen

Buraschi

et al. 2020

Journal of Biological Chemistry

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Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

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Section: Discussionmentioning

confidence: 99%

Catabolic degradation of endothelial VEGFA via autophagy

Neill

Chen

Buraschi

et al. 2020

Journal of Biological Chemistry

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“…Observational studies have found a decreased risk of breast cancer death associated with statin-use [41, 42], although no definitive cause-effect relationships have been reported. Pre-clinical research has demonstrated anti-breast cancer activity in either caloric restriction or intermittent fasting [43–46], and we have demonstrated therapeutic synergy between caloric restriction and radiotherapy in animal models [11, 27]. A fundamental concern with the clinical translation of therapeutic caloric restriction, however, is adherence.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies implicate obesity as a driver of a number of the hallmarks of cancer. Obesity-related increases in IGF-1R signaling augment breast cancer cell proliferation and decrease apoptosis [11]. The consequential chronic inflammatory state caused by obesity facilitates immune dysregulation and angiogenesis [12].…”

Section: Introductionmentioning

confidence: 99%

Onco-metabolism: defining the prognostic significance of obesity and diabetes in women with brain metastases from breast cancer

McCall

Simone

Mehta

et al. 2018

Breast Cancer Res Treat

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“…Finally, 2 studies investigating the combination of 30% CR and IR in triple-negative breast cancer models have revealed synergistic anti-tumor effects that were related to a downregulation of the IGF-1 receptor (IGF-1R) and its downstream targets Akt and phosphoinositide 3-kinase (PI3K) in both primary tumors and metastases [102,103]. Although ketone bodies were not measured, these findings suggest an intriguing role for ketogenic therapy as a targeted therapy against the IGF-1R pathway in order to sensitize tumor cells against IR.…”

Section: Combining Ketogenic Metabolic Therapy With Radiotherapy To Ementioning

confidence: 99%

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

Klement¹

2017

Complement Med Res

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Radiotherapy (RT) is a mainstay in the treatment of solid tumors and works by physicochemical reactions inducing oxidative stress in cells. Because in practice the efficacy of RT is limited by its toxicity to normal tissues, any strategy that selectively increases the radiosensitivity of tumor cells or boosts the radioresistance of normal cells is a valuable adjunct to RT. In this review, I summarize preclinical and clinical data supporting the hypothesis that ketogenic therapy through fasting and/or ketogenic diets can be utilized as such an adjunct in order to improve the outcome after RT, in terms of both higher tumor control and lower normal-tissue complication probability. The first effect relates to the metabolic shift from glycolysis towards mitochondrial metabolism, which selectively increases reactive oxygen species (ROS) production and impairs adenoside triphosphate (ATP) production in tumor cells. The second effect is based on the differential stress resistance phenomenon describing the reprogramming of normal cells, but not tumor cells, from proliferation towards maintenance and stress resistance when glucose and growth factor levels are decreased and ketone body levels are elevated. Underlying both effects are metabolic differences between normal and tumor cells. Ketogenic therapy is a non-toxic and cost-effective complementary treatment option that exploits these differences and deserves further clinical investigation.

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Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer

Cited by 50 publications

References 39 publications

Catabolic degradation of endothelial VEGFA via autophagy

Catabolic degradation of endothelial VEGFA via autophagy

Onco-metabolism: defining the prognostic significance of obesity and diabetes in women with brain metastases from breast cancer

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

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