Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers
Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramm...
Gespeichert in:
| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2020-04, Vol.80 (8), p.1630-1643 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1643 |
|---|---|
| container_issue | 8 |
| container_start_page | 1630 |
| container_title | Cancer research (Chicago, Ill.) |
| container_volume | 80 |
| creator | Mukhopadhyay, Suman Goswami, Debanjan Adiseshaiah, Pavan P Burgan, William Yi, Ming Guerin, Theresa M Kozlov, Serguei V Nissley, Dwight V McCormick, Frank |
| description | Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg. |
| doi_str_mv | 10.1158/0008-5472.CAN-19-1363 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7185043</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2334696248</sourcerecordid><originalsourceid>FETCH-LOGICAL-c581t-ddcc1b49ffb93633b731f036bcf67100a873035250dc9aca53e2b97e100116c13</originalsourceid><addsrcrecordid>eNpVkVtv2yAUx9G0qU0vH2EVj3txxzHGl5dJmXvZtCitetEeEcbHDZUNKTiR8u2H1SzanoDzvwD6EfIZ2CWAKL8yxspEZEV6Wc-XCVQJ8Jx_IDMQvEyKLBMfyezgOSYnIbzGowAmjsgxhyqWCDYj22fboh-MNfaF3vabUcW963fBBPrd9WFEH2i9wsGNK_RqvaO_V6ZHuny4Sem9d3GOe4PHGBqV1UiNpb8e5o_JlTdbtPQ-Dj2q0WhaT7oPZ-RTp_qA5_v1lDzfXD_VP5LF3e3Per5ItChhTNpWa2iyquuaKn6PNwWHjvG80V1eAGOqLDjjIhWs1ZXSSnBMm6rAKAHkGvgp-fbeu940A7Ya7ehVL9feDMrvpFNG_q9Ys5IvbisLKAXLeCz4si_w7m2DYZSDCRr7Xll0myBTzrO8ytOsjFbxbtXeheCxO1wDTE7M5MRDTjxkZCahkhOzmLv4942H1F9I_A-A_JTp</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2334696248</pqid></control><display><type>article</type><title>Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Mukhopadhyay, Suman ; Goswami, Debanjan ; Adiseshaiah, Pavan P ; Burgan, William ; Yi, Ming ; Guerin, Theresa M ; Kozlov, Serguei V ; Nissley, Dwight V ; McCormick, Frank</creator><creatorcontrib>Mukhopadhyay, Suman ; Goswami, Debanjan ; Adiseshaiah, Pavan P ; Burgan, William ; Yi, Ming ; Guerin, Theresa M ; Kozlov, Serguei V ; Nissley, Dwight V ; McCormick, Frank</creatorcontrib><description>Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.</description><identifier>ISSN: 0008-5472</identifier><identifier>ISSN: 1538-7445</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-19-1363</identifier><identifier>PMID: 31911550</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antimetabolites, Antineoplastic - pharmacology ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - mortality ; Cell Line, Tumor ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacology ; Drug Resistance, Neoplasm - physiology ; Gemcitabine ; Glutaminase - antagonists & inhibitors ; Glutamine - metabolism ; Heterografts ; Humans ; Mice ; Mice, Nude ; Mutation ; Neoplasm Proteins - metabolism ; NF-E2-Related Factor 2 - metabolism ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - mortality ; Prognosis ; Proto-Oncogene Proteins p21(ras) - genetics ; Random Allocation ; Tissue Array Analysis ; Up-Regulation</subject><ispartof>Cancer research (Chicago, Ill.), 2020-04, Vol.80 (8), p.1630-1643</ispartof><rights>2020 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c581t-ddcc1b49ffb93633b731f036bcf67100a873035250dc9aca53e2b97e100116c13</citedby><cites>FETCH-LOGICAL-c581t-ddcc1b49ffb93633b731f036bcf67100a873035250dc9aca53e2b97e100116c13</cites><orcidid>0000-0001-9098-1364 ; 0000-0001-5910-3811</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3354,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31911550$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mukhopadhyay, Suman</creatorcontrib><creatorcontrib>Goswami, Debanjan</creatorcontrib><creatorcontrib>Adiseshaiah, Pavan P</creatorcontrib><creatorcontrib>Burgan, William</creatorcontrib><creatorcontrib>Yi, Ming</creatorcontrib><creatorcontrib>Guerin, Theresa M</creatorcontrib><creatorcontrib>Kozlov, Serguei V</creatorcontrib><creatorcontrib>Nissley, Dwight V</creatorcontrib><creatorcontrib>McCormick, Frank</creatorcontrib><title>Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.</description><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - mortality</subject><subject>Cell Line, Tumor</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - pharmacology</subject><subject>Drug Resistance, Neoplasm - physiology</subject><subject>Gemcitabine</subject><subject>Glutaminase - antagonists & inhibitors</subject><subject>Glutamine - metabolism</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mutation</subject><subject>Neoplasm Proteins - metabolism</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Prognosis</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Random Allocation</subject><subject>Tissue Array Analysis</subject><subject>Up-Regulation</subject><issn>0008-5472</issn><issn>1538-7445</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkVtv2yAUx9G0qU0vH2EVj3txxzHGl5dJmXvZtCitetEeEcbHDZUNKTiR8u2H1SzanoDzvwD6EfIZ2CWAKL8yxspEZEV6Wc-XCVQJ8Jx_IDMQvEyKLBMfyezgOSYnIbzGowAmjsgxhyqWCDYj22fboh-MNfaF3vabUcW963fBBPrd9WFEH2i9wsGNK_RqvaO_V6ZHuny4Sem9d3GOe4PHGBqV1UiNpb8e5o_JlTdbtPQ-Dj2q0WhaT7oPZ-RTp_qA5_v1lDzfXD_VP5LF3e3Per5ItChhTNpWa2iyquuaKn6PNwWHjvG80V1eAGOqLDjjIhWs1ZXSSnBMm6rAKAHkGvgp-fbeu940A7Ya7ehVL9feDMrvpFNG_q9Ys5IvbisLKAXLeCz4si_w7m2DYZSDCRr7Xll0myBTzrO8ytOsjFbxbtXeheCxO1wDTE7M5MRDTjxkZCahkhOzmLv4942H1F9I_A-A_JTp</recordid><startdate>20200415</startdate><enddate>20200415</enddate><creator>Mukhopadhyay, Suman</creator><creator>Goswami, Debanjan</creator><creator>Adiseshaiah, Pavan P</creator><creator>Burgan, William</creator><creator>Yi, Ming</creator><creator>Guerin, Theresa M</creator><creator>Kozlov, Serguei V</creator><creator>Nissley, Dwight V</creator><creator>McCormick, Frank</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9098-1364</orcidid><orcidid>https://orcid.org/0000-0001-5910-3811</orcidid></search><sort><creationdate>20200415</creationdate><title>Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers</title><author>Mukhopadhyay, Suman ; Goswami, Debanjan ; Adiseshaiah, Pavan P ; Burgan, William ; Yi, Ming ; Guerin, Theresa M ; Kozlov, Serguei V ; Nissley, Dwight V ; McCormick, Frank</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c581t-ddcc1b49ffb93633b731f036bcf67100a873035250dc9aca53e2b97e100116c13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - metabolism</topic><topic>Carcinoma, Pancreatic Ductal - mortality</topic><topic>Cell Line, Tumor</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - pharmacology</topic><topic>Drug Resistance, Neoplasm - physiology</topic><topic>Gemcitabine</topic><topic>Glutaminase - antagonists & inhibitors</topic><topic>Glutamine - metabolism</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mutation</topic><topic>Neoplasm Proteins - metabolism</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Prognosis</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Random Allocation</topic><topic>Tissue Array Analysis</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mukhopadhyay, Suman</creatorcontrib><creatorcontrib>Goswami, Debanjan</creatorcontrib><creatorcontrib>Adiseshaiah, Pavan P</creatorcontrib><creatorcontrib>Burgan, William</creatorcontrib><creatorcontrib>Yi, Ming</creatorcontrib><creatorcontrib>Guerin, Theresa M</creatorcontrib><creatorcontrib>Kozlov, Serguei V</creatorcontrib><creatorcontrib>Nissley, Dwight V</creatorcontrib><creatorcontrib>McCormick, Frank</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mukhopadhyay, Suman</au><au>Goswami, Debanjan</au><au>Adiseshaiah, Pavan P</au><au>Burgan, William</au><au>Yi, Ming</au><au>Guerin, Theresa M</au><au>Kozlov, Serguei V</au><au>Nissley, Dwight V</au><au>McCormick, Frank</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2020-04-15</date><risdate>2020</risdate><volume>80</volume><issue>8</issue><spage>1630</spage><epage>1643</epage><pages>1630-1643</pages><issn>0008-5472</issn><issn>1538-7445</issn><eissn>1538-7445</eissn><abstract>Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation. SIGNIFICANCE: These findings illuminate the mechanistic features of KRAS-mediated chemoresistance and provide a rationale for exploiting metabolic reprogramming in pancreatic cancer cells to confer therapeutic opportunities that could be translated into clinical trials. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/8/1630/F1.large.jpg.</abstract><cop>United States</cop><pmid>31911550</pmid><doi>10.1158/0008-5472.CAN-19-1363</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-9098-1364</orcidid><orcidid>https://orcid.org/0000-0001-5910-3811</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2020-04, Vol.80 (8), p.1630-1643 |
| issn | 0008-5472 1538-7445 1538-7445 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7185043 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antimetabolites, Antineoplastic - pharmacology Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - mortality Cell Line, Tumor Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Drug Resistance, Neoplasm - physiology Gemcitabine Glutaminase - antagonists & inhibitors Glutamine - metabolism Heterografts Humans Mice Mice, Nude Mutation Neoplasm Proteins - metabolism NF-E2-Related Factor 2 - metabolism Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - mortality Prognosis Proto-Oncogene Proteins p21(ras) - genetics Random Allocation Tissue Array Analysis Up-Regulation |
| title | Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T10%3A20%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Undermining%20Glutaminolysis%20Bolsters%20Chemotherapy%20While%20NRF2%20Promotes%20Chemoresistance%20in%20KRAS-Driven%20Pancreatic%20Cancers&rft.jtitle=Cancer%20research%20(Chicago,%20Ill.)&rft.au=Mukhopadhyay,%20Suman&rft.date=2020-04-15&rft.volume=80&rft.issue=8&rft.spage=1630&rft.epage=1643&rft.pages=1630-1643&rft.issn=0008-5472&rft.eissn=1538-7445&rft_id=info:doi/10.1158/0008-5472.CAN-19-1363&rft_dat=%3Cproquest_pubme%3E2334696248%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2334696248&rft_id=info:pmid/31911550&rfr_iscdi=true |