Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1a

Sangbin Lim; Hao Liu; Luciana Madeira Da Silva; Ritu Arora; Zixing Liu; Joshua B. Phillips; David C. Schmitt; Tung Vu; Steven Mcclellan; Yifeng Lin; Wensheng Lin; Gary A. Piazza; Oystein Fodstad; Ming Tan

doi:10.1158/0008-5472.CAN-15-1538

Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1a

Sangbin Lim, Hao Liu, Luciana Madeira Da Silva, Ritu Arora, Zixing Liu, Joshua B. Phillips, David C. Schmitt, Tung Vu, Steven Mcclellan, Yifeng Lin, Wensheng Lin, Gary A. Piazza, Oystein Fodstad, Ming Tan

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114 Scopus citations

Abstract

B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo.We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1a and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1a by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.

Original language	English (US)
Pages (from-to)	2231-2242
Number of pages	12
Journal	Cancer Research
Volume	76
Issue number	8
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-1538
State	Published - Apr 15 2016

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Publisher Copyright:
©2016 American Association for Cancer Research.

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Lim, S., Liu, H., Da Silva, L. M., Arora, R., Liu, Z., Phillips, J. B., Schmitt, D. C., Vu, T., Mcclellan, S., Lin, Y., Lin, W., Piazza, G. A., Fodstad, O., & Tan, M. (2016). Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1a. Cancer Research, 76(8), 2231-2242. https://doi.org/10.1158/0008-5472.CAN-15-1538

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title = "Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1a",

abstract = "B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo.We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1a and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1a by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.",

author = "Sangbin Lim and Hao Liu and {Da Silva}, {Luciana Madeira} and Ritu Arora and Zixing Liu and Phillips, {Joshua B.} and Schmitt, {David C.} and Tung Vu and Steven Mcclellan and Yifeng Lin and Wensheng Lin and Piazza, {Gary A.} and Oystein Fodstad and Ming Tan",

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doi = "10.1158/0008-5472.CAN-15-1538",

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AU - Lim, Sangbin

AU - Liu, Hao

AU - Da Silva, Luciana Madeira

AU - Arora, Ritu

AU - Liu, Zixing

AU - Phillips, Joshua B.

AU - Schmitt, David C.

AU - Vu, Tung

AU - Mcclellan, Steven

AU - Lin, Yifeng

AU - Lin, Wensheng

AU - Piazza, Gary A.

AU - Fodstad, Oystein

AU - Tan, Ming

PY - 2016/4/15

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N2 - B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo.We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1a and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1a by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.

AB - B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo.We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1a and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1a by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression.

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Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1a

Abstract

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