Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling

Dong, Liuyi; Yuan, Ye; Opansky, C.; Chen, Yiliang; Aguilera-Barrantes, Irene; Wu, Shiyong; Yuan, Rong; Cao, Qi; Cheng, Yee Chung; Sahoo, Daisy; Silverstein, Roy L.; Ren, Bin

doi:10.18632/oncotarget.15123

Cited by 30 publications

(59 citation statements)

References 63 publications

(114 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A subpopulation of cancer cells with high CD36 expression has unique metastasis-initiating potential, highlighting a key role of CD36-regulated lipid metabolism and signaling in metastatic colonization (45). Lysophosphatidic acid/protein kinase D1/CD36 signaling is a bona fide breast cancer promoter via stimulating microvascular remodeling in chronic diet-induced obesity (46). CD36-positive Blymphoblasts predict poor outcome in children with B-lymphoblastic leukemia (47).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Sun

Tan

Huang

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

show abstract

Section: Discussionmentioning

confidence: 99%

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Sun

Tan

Huang

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recently, findings from cell culture and animal models identified obesity as a main contributing factor in the underlying pathophysiology implicated in the development of breast cancer chemotherapeutic drug resistance (16,17). Patients suffering from obesity and breast cancer presented with poor clinical outcomes when treated with first line adjuvant regimens such as doxorubicin (18,19).…”

Section: Introductionmentioning

confidence: 99%

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

et al. 2020

View full text Add to dashboard Cite

Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.

show abstract

“…Intriguingly, FoxO1 can regulate the transcription of CD36 in microvascular endothelial cells and tumor‐associated endothelial cells . Changes in CD36 transcription are implicated in endothelial cell differentiation in response to signaling initiated by lysophosphatidic acid, a lipid signaling mediator, and protein kinase D1 . CD36 is known as an angiogenic regulator and fatty acid receptor .…”

mentioning

confidence: 99%

“…FoxO1 may thus promote fatty acid uptake and metabolism in endothelial cells, likely regulating angiogenesis by coupling metabolic reprogramming with angiogenic gene expression. Importantly, FoxO1 may regulate the formation of functional vascular networks via priming pro‐angiogenic VEGF signaling through downregulating anti‐angiogenic CD36 signaling in the presence of lysophosphatidic acid . By showing that FoxO1 promotes VEGF expression in keratinocytes, the studies from Jeon et al add an additional layer to FoxO1 regulation of angiogenesis, even though the precise mechanisms are not yet understood (Figure ).…”

mentioning

confidence: 99%

“…Taken together, these studies provide strong evidence that FoxO1 significantly contributes to the regulation of vascular maturation, leading to functional angiogenesis through the stepwise transition from an actively growing vascular bed to a quiescent, fully formed and functional network by recruitment of pericytes or vascular smooth muscle cells. In fact, FoxO1 has emerged as a key regulator of endothelial cell functions and functional angiogenesis .…”

mentioning

confidence: 99%

See 1 more Smart Citation

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

Ren

2018

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

FoxO1 has emerged as an important regulator of angiogenesis. Recent work published in this Journal shows that FoxO1 regulates VEGF expression in keratinocytes and is required for angiogenesis in wound healing. Since FoxO1 also regulates CD36 transcription, and endothelial cell differentiation and vascular maturation, this transcription factor may be essential for the formation of functional vascular networks via coupling the regulation of CD36 in vascular endothelial cells under physiological and pathological conditions. Although many outstanding questions remain to be answered, the mechanisms by which FoxO1 regulates VEGF in keratinocytes provide insight into the development of functional angiogenesis and further our understanding of vascular biology. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling

Cited by 30 publications

References 63 publications

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

Contact Info

Product

Resources

About