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Hexokinase 2: The preferential target of trehalose‐6‐phosphate over hexokinase 1
Cancer‐related metabolic features are in part maintained by hexokinase 2 upregulation, which leads to high levels of glucose‐6‐phosphate (G6P) and is needed to provide energy and biomass to support rapid proliferation. Using a humanized model of the yeast Saccharomyces cerevisiae, we explored how hu...
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| Published in: | Journal of cellular biochemistry 2022-11, Vol.123 (11), p.1808-1816 |
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| creator | Magalhães, Rayne S. S. Boechat, Fernanda C. Brasil, Aline A. Neto, José. R. M. Ribeiro, Gabriela D. Paranhos, Luan H. Neves de Souza, Natália Vieira, Tuane Outeiro, Tiago F. Neves, Bianca C. Eleutherio, Elis C. A. |
| description | Cancer‐related metabolic features are in part maintained by hexokinase 2 upregulation, which leads to high levels of glucose‐6‐phosphate (G6P) and is needed to provide energy and biomass to support rapid proliferation. Using a humanized model of the yeast Saccharomyces cerevisiae, we explored how human hexokinase 2 (HK2) behaves under different nutritional conditions. At high glucose levels, yeast presents aerobic glycolysis through a regulatory mechanism known as catabolic repression, which exerts a metabolic adaptation like the Warburg effect. At high glucose concentrations, HK2 did not translocate into the nucleus and was not able to shift the metabolism toward a highly glycolytic state, in contrast to the effect of yeast hexokinase 2 (Hxk2), which is a crucial protein for the control of aerobic glycolysis in S. cerevisiae. During the stationary phase, when glucose is exhausted, Hxk2 is shuttled out of the nucleus, ceasing catabolic repression. Cells harvested at this condition display low glucose consumption rates. However, glucose‐starved cells expressing HK2 had an increased capacity to consume glucose. In those cells, HK2 localized to mitochondria, becoming insensitive to G6P inhibition. We also found that the sugar trehalose‐6‐phosphate (T6P) is a human HK2 inhibitor, like yeast Hxk2, but was not able to inhibit human HK1, the isoform that is ubiquitously expressed in almost all mammalian tissues. In contrast to G6P, T6P inhibited HK2 even when HK2 was associated with mitochondria. The binding of HK2 to mitochondria is crucial for cancer survival and proliferation. T6P was able to reduce the cell viability of tumor cells, although its toxicity was not impressive. This was expected as cell absorption of phosphorylated sugars is low, which might be counteracted using nanotechnology. Altogether, these data suggest that T6P may offer a new paradigm for cancer treatment based on specific inhibition of HK2. |
| doi_str_mv | 10.1002/jcb.30317 |
| format | article |
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S. ; Boechat, Fernanda C. ; Brasil, Aline A. ; Neto, José. R. M. ; Ribeiro, Gabriela D. ; Paranhos, Luan H. ; Neves de Souza, Natália ; Vieira, Tuane ; Outeiro, Tiago F. ; Neves, Bianca C. ; Eleutherio, Elis C. A.</creator><creatorcontrib>Magalhães, Rayne S. S. ; Boechat, Fernanda C. ; Brasil, Aline A. ; Neto, José. R. M. ; Ribeiro, Gabriela D. ; Paranhos, Luan H. ; Neves de Souza, Natália ; Vieira, Tuane ; Outeiro, Tiago F. ; Neves, Bianca C. ; Eleutherio, Elis C. A.</creatorcontrib><description>Cancer‐related metabolic features are in part maintained by hexokinase 2 upregulation, which leads to high levels of glucose‐6‐phosphate (G6P) and is needed to provide energy and biomass to support rapid proliferation. Using a humanized model of the yeast Saccharomyces cerevisiae, we explored how human hexokinase 2 (HK2) behaves under different nutritional conditions. At high glucose levels, yeast presents aerobic glycolysis through a regulatory mechanism known as catabolic repression, which exerts a metabolic adaptation like the Warburg effect. At high glucose concentrations, HK2 did not translocate into the nucleus and was not able to shift the metabolism toward a highly glycolytic state, in contrast to the effect of yeast hexokinase 2 (Hxk2), which is a crucial protein for the control of aerobic glycolysis in S. cerevisiae. During the stationary phase, when glucose is exhausted, Hxk2 is shuttled out of the nucleus, ceasing catabolic repression. Cells harvested at this condition display low glucose consumption rates. However, glucose‐starved cells expressing HK2 had an increased capacity to consume glucose. In those cells, HK2 localized to mitochondria, becoming insensitive to G6P inhibition. We also found that the sugar trehalose‐6‐phosphate (T6P) is a human HK2 inhibitor, like yeast Hxk2, but was not able to inhibit human HK1, the isoform that is ubiquitously expressed in almost all mammalian tissues. In contrast to G6P, T6P inhibited HK2 even when HK2 was associated with mitochondria. The binding of HK2 to mitochondria is crucial for cancer survival and proliferation. T6P was able to reduce the cell viability of tumor cells, although its toxicity was not impressive. This was expected as cell absorption of phosphorylated sugars is low, which might be counteracted using nanotechnology. Altogether, these data suggest that T6P may offer a new paradigm for cancer treatment based on specific inhibition of HK2.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.30317</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc</publisher><subject>aerobic glycolysis ; Biomass energy production ; Cancer ; Cell proliferation ; Cell viability ; Glucose ; Glycolysis ; Hexokinase ; hexokinase 2 ; Metabolism ; Mitochondria ; Nanotechnology ; Nuclei (cytology) ; Regulatory mechanisms (biology) ; Saccharomyces cerevisiae ; Stationary phase ; Sugar ; Toxicity ; Trehalose ; trehalose‐6‐phosphate inhibitor ; Tumor cells ; Yeast ; Yeasts</subject><ispartof>Journal of cellular biochemistry, 2022-11, Vol.123 (11), p.1808-1816</ispartof><rights>2022 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3307-7e5d99e38e9a0181dd1628383b753ed091059110e426d5505b4a2fb7b292ce683</citedby><cites>FETCH-LOGICAL-c3307-7e5d99e38e9a0181dd1628383b753ed091059110e426d5505b4a2fb7b292ce683</cites><orcidid>0000-0001-5842-2714</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcb.30317$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.30317$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids></links><search><creatorcontrib>Magalhães, Rayne S. S.</creatorcontrib><creatorcontrib>Boechat, Fernanda C.</creatorcontrib><creatorcontrib>Brasil, Aline A.</creatorcontrib><creatorcontrib>Neto, José. R. M.</creatorcontrib><creatorcontrib>Ribeiro, Gabriela D.</creatorcontrib><creatorcontrib>Paranhos, Luan H.</creatorcontrib><creatorcontrib>Neves de Souza, Natália</creatorcontrib><creatorcontrib>Vieira, Tuane</creatorcontrib><creatorcontrib>Outeiro, Tiago F.</creatorcontrib><creatorcontrib>Neves, Bianca C.</creatorcontrib><creatorcontrib>Eleutherio, Elis C. A.</creatorcontrib><title>Hexokinase 2: The preferential target of trehalose‐6‐phosphate over hexokinase 1</title><title>Journal of cellular biochemistry</title><description>Cancer‐related metabolic features are in part maintained by hexokinase 2 upregulation, which leads to high levels of glucose‐6‐phosphate (G6P) and is needed to provide energy and biomass to support rapid proliferation. Using a humanized model of the yeast Saccharomyces cerevisiae, we explored how human hexokinase 2 (HK2) behaves under different nutritional conditions. At high glucose levels, yeast presents aerobic glycolysis through a regulatory mechanism known as catabolic repression, which exerts a metabolic adaptation like the Warburg effect. At high glucose concentrations, HK2 did not translocate into the nucleus and was not able to shift the metabolism toward a highly glycolytic state, in contrast to the effect of yeast hexokinase 2 (Hxk2), which is a crucial protein for the control of aerobic glycolysis in S. cerevisiae. During the stationary phase, when glucose is exhausted, Hxk2 is shuttled out of the nucleus, ceasing catabolic repression. Cells harvested at this condition display low glucose consumption rates. However, glucose‐starved cells expressing HK2 had an increased capacity to consume glucose. In those cells, HK2 localized to mitochondria, becoming insensitive to G6P inhibition. We also found that the sugar trehalose‐6‐phosphate (T6P) is a human HK2 inhibitor, like yeast Hxk2, but was not able to inhibit human HK1, the isoform that is ubiquitously expressed in almost all mammalian tissues. In contrast to G6P, T6P inhibited HK2 even when HK2 was associated with mitochondria. The binding of HK2 to mitochondria is crucial for cancer survival and proliferation. T6P was able to reduce the cell viability of tumor cells, although its toxicity was not impressive. This was expected as cell absorption of phosphorylated sugars is low, which might be counteracted using nanotechnology. Altogether, these data suggest that T6P may offer a new paradigm for cancer treatment based on specific inhibition of HK2.</description><subject>aerobic glycolysis</subject><subject>Biomass energy production</subject><subject>Cancer</subject><subject>Cell proliferation</subject><subject>Cell viability</subject><subject>Glucose</subject><subject>Glycolysis</subject><subject>Hexokinase</subject><subject>hexokinase 2</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Nanotechnology</subject><subject>Nuclei (cytology)</subject><subject>Regulatory mechanisms (biology)</subject><subject>Saccharomyces cerevisiae</subject><subject>Stationary phase</subject><subject>Sugar</subject><subject>Toxicity</subject><subject>Trehalose</subject><subject>trehalose‐6‐phosphate inhibitor</subject><subject>Tumor cells</subject><subject>Yeast</subject><subject>Yeasts</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp10LFOwzAQBmALgUQpDLyBJRYYUs52HMdsUAEFVWIpc-QkF5KSxsFOgW48As_IkxAIEhISw-mW736dfkIOGUwYAD9dZulEgGBqi4wYaBWEURhukxEoAQEXjO-SPe-XAKC14COymOGrfawa45HyM7ookbYOC3TYdJWpaWfcA3bUFrRzWJraevx4e4_6aUvr29J0SO0zOlr-5rB9slOY2uPBzx6T-6vLxXQWzO-ub6bn8yATAlSgUOZao4hRG2Axy3MW8VjEIlVSYA6agdSMAYY8yqUEmYaGF6lKueYZRrEYk-Mht3X2aY2-S1aVz7CuTYN27ROuAKJQhJr19OgPXdq1a_rveiUUC6Vkslcng8qc9b7vIWldtTJukzBIvvpN-n6T7357ezrYl6rGzf8wuZ1eDBef_Wt7pQ</recordid><startdate>202211</startdate><enddate>202211</enddate><creator>Magalhães, Rayne S. S.</creator><creator>Boechat, Fernanda C.</creator><creator>Brasil, Aline A.</creator><creator>Neto, José. R. M.</creator><creator>Ribeiro, Gabriela D.</creator><creator>Paranhos, Luan H.</creator><creator>Neves de Souza, Natália</creator><creator>Vieira, Tuane</creator><creator>Outeiro, Tiago F.</creator><creator>Neves, Bianca C.</creator><creator>Eleutherio, Elis C. A.</creator><general>Wiley Subscription Services, Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5842-2714</orcidid></search><sort><creationdate>202211</creationdate><title>Hexokinase 2: The preferential target of trehalose‐6‐phosphate over hexokinase 1</title><author>Magalhães, Rayne S. S. ; Boechat, Fernanda C. ; Brasil, Aline A. ; Neto, José. R. M. ; Ribeiro, Gabriela D. ; Paranhos, Luan H. ; Neves de Souza, Natália ; Vieira, Tuane ; Outeiro, Tiago F. ; Neves, Bianca C. ; Eleutherio, Elis C. 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S.</au><au>Boechat, Fernanda C.</au><au>Brasil, Aline A.</au><au>Neto, José. R. M.</au><au>Ribeiro, Gabriela D.</au><au>Paranhos, Luan H.</au><au>Neves de Souza, Natália</au><au>Vieira, Tuane</au><au>Outeiro, Tiago F.</au><au>Neves, Bianca C.</au><au>Eleutherio, Elis C. A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hexokinase 2: The preferential target of trehalose‐6‐phosphate over hexokinase 1</atitle><jtitle>Journal of cellular biochemistry</jtitle><date>2022-11</date><risdate>2022</risdate><volume>123</volume><issue>11</issue><spage>1808</spage><epage>1816</epage><pages>1808-1816</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Cancer‐related metabolic features are in part maintained by hexokinase 2 upregulation, which leads to high levels of glucose‐6‐phosphate (G6P) and is needed to provide energy and biomass to support rapid proliferation. Using a humanized model of the yeast Saccharomyces cerevisiae, we explored how human hexokinase 2 (HK2) behaves under different nutritional conditions. At high glucose levels, yeast presents aerobic glycolysis through a regulatory mechanism known as catabolic repression, which exerts a metabolic adaptation like the Warburg effect. At high glucose concentrations, HK2 did not translocate into the nucleus and was not able to shift the metabolism toward a highly glycolytic state, in contrast to the effect of yeast hexokinase 2 (Hxk2), which is a crucial protein for the control of aerobic glycolysis in S. cerevisiae. During the stationary phase, when glucose is exhausted, Hxk2 is shuttled out of the nucleus, ceasing catabolic repression. Cells harvested at this condition display low glucose consumption rates. However, glucose‐starved cells expressing HK2 had an increased capacity to consume glucose. In those cells, HK2 localized to mitochondria, becoming insensitive to G6P inhibition. We also found that the sugar trehalose‐6‐phosphate (T6P) is a human HK2 inhibitor, like yeast Hxk2, but was not able to inhibit human HK1, the isoform that is ubiquitously expressed in almost all mammalian tissues. In contrast to G6P, T6P inhibited HK2 even when HK2 was associated with mitochondria. The binding of HK2 to mitochondria is crucial for cancer survival and proliferation. T6P was able to reduce the cell viability of tumor cells, although its toxicity was not impressive. This was expected as cell absorption of phosphorylated sugars is low, which might be counteracted using nanotechnology. Altogether, these data suggest that T6P may offer a new paradigm for cancer treatment based on specific inhibition of HK2.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1002/jcb.30317</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-5842-2714</orcidid></addata></record> |
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| subjects | aerobic glycolysis Biomass energy production Cancer Cell proliferation Cell viability Glucose Glycolysis Hexokinase hexokinase 2 Metabolism Mitochondria Nanotechnology Nuclei (cytology) Regulatory mechanisms (biology) Saccharomyces cerevisiae Stationary phase Sugar Toxicity Trehalose trehalose‐6‐phosphate inhibitor Tumor cells Yeast Yeasts |
| title | Hexokinase 2: The preferential target of trehalose‐6‐phosphate over hexokinase 1 |
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