GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

Kuang, Ruby; Jahangiri, Arman; Mascharak, Smita; Nguyen, Alan; Chandra, Ankush; Flanigan, Patrick M.; Yagnik, Garima; Wagner, Jeffrey; Lay, Michael De; Carrera, Diego; Castro, Brandyn; Hayes, Josie; Sidorov, Maxim; Izquierdo-García, José Luis; Eriksson, Per; Ronen, Sabrina M.; Phillips, Joanna J.; Molinaro, Annette M.; Koliwad, Suneil K.; Aghi, Manish K.

doi:10.1172/jci.insight.88815

Cited by 51 publications

(51 citation statements)

References 32 publications

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“…Indeed, this devascularization succeeds despite upregulation of compensatory VEGF-independent pro-angiogenic pathways and despite enriched neurosphere yield in BRGs and bevacizumab-resistant xenografts and expression of genes associated with glioma stem cells, which have previously been shown to be capable of forming endothelial cells (22). This successful devascularization led to increased hypoxia in our resistance model, with an associated upregulation of genes involved in metabolism and inflammation, consistent with changes reported elsewhere (23)(24)(25).…”

Section: Discussionsupporting

confidence: 83%

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Jahangiri

Chen

Chandra

et al. 2018

Preprint

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Bevacizumab treatment of glioblastoma is limited by transient responses and acquired resistance. Because of the lengthy duration of treatment that can precede resistance in patients, in order to study changes underlying the evolution of bevacizumab resistance, we created a novel multigenerational xenograft model of acquired bevacizumab resistance. Glioblastoma xenografts were treated with bevacizumab or IgG, and the fastest growing tumor reimplanted into new mice, generating paired isogeneic responsive or resistant multigenerational xenografts. Microarray analysis revealed significant overexpression across generations of the mesenchymal subtype gene signature, paralleling results from patient bevacizumab-resistant gliobalstomas (BRGs) that exhibited increasing mesenchymal gene expression correlating with increased bevacizumab treatment duration. Key mesenchymal markers, including YKL-40, CD44, SERPINE1, and TIMP1 were upregulated across generations, with altered morphology, increased invasiveness, and increased neurosphere formation confirmed in later xenograft generations. Interestingly, YKL-40 levels were elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas (52.4 vs. 24.2 ng/mL; P<0.05). Finally, despite upregulation of VEGF-independent pro-angiogenic genes across xenograft generations, immunostaining revealed increased hypoxia and decreased vessel density with increasing generation of treatment, mirroring our findings in patient BRGs and suggesting tumor growth despite effective devascularization caused by VEGF blockade. Besides identifying novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work suggests YKL-40 as a blood biomarker of bevacizumab resistance worthy of further evaluation.

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Section: Discussionsupporting

confidence: 83%

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Jahangiri

Chen

Chandra

et al. 2018

Preprint

Self Cite

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“…7,8 Indeed, GLUT3 has been reported as a potential target for anticancer therapy. 38 Our novel findings show that GLUT3 is positively regulated by YY1, which is highly expressed in various tumors, and, thus, elucidate a novel pathway for GLUT3 upregulation in tumor cells. Furthermore, these results indicate that a GLUT3-targeting therapeutic strategy could be achieved by targeting YY1.…”

Section: Discussionmentioning

confidence: 69%

“…The critical roles of GLUT3 are most plausibly due to its high activity as a glucose transporter, with higher affinity for glucose than other Class I GLUT family members, including the widely expressed GLUT1 . Indeed, GLUT3 has been reported as a potential target for anticancer therapy . Our novel findings show that GLUT3 is positively regulated by YY1, which is highly expressed in various tumors, and, thus, elucidate a novel pathway for GLUT3 upregulation in tumor cells.…”

Section: Discussionmentioning

confidence: 71%

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3

Wang

Huang

et al. 2018

Cancer Science

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Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family‐mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1‐induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53‐independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.

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“…One possible reason is that many cancer cell lines have an increased expression of glucose transporters . In the U‐87 tumor line, it has been reported that GLUT‐3 are overexpressed which is the largest transporter in the brain with a 5‐times greater transport capacity . This increased GLUT‐3 expression in tumor areas as compared to the normal brain provides a compelling reason for the improved contrast between the brain and the tumor for 3‐OMG versus D‐glucose.…”

Section: Discussionmentioning

confidence: 99%

CEST MRI of 3‐O‐methyl‐D‐glucose uptake and accumulation in brain tumors

Sehgal

Lal

et al. 2018

Magnetic Resonance in Med

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GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

Cited by 51 publications

References 32 publications

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3

CEST MRI of 3‐O‐methyl‐D‐glucose uptake and accumulation in brain tumors

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