Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations
KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regu...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S147655862200063X |
| _version_ | 1818032948773912576 |
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| author | Dat P. Ha Bo Huang Han Wang Daisy Flores Rangel Richard Van Krieken Ze Liu Soma Samanta Nouri Neamati Amy S. Lee |
| author_facet | Dat P. Ha Bo Huang Han Wang Daisy Flores Rangel Richard Van Krieken Ze Liu Soma Samanta Nouri Neamati Amy S. Lee |
| author_sort | Dat P. Ha |
| collection | DOAJ |
| description | KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRASG12D-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms. Here, we report that knockdown of GRP78 via siRNA reduced oncogenic KRAS protein level in human lung, colon, and pancreatic cancer cells bearing various KRAS mutations. This effect was at the post-transcriptional level and is independent of proteasomal degradation or autophagy. Moreover, targeting GRP78 via small molecule inhibitors such as HA15 and YUM70 with anti-cancer activities while sparing normal cells significantly suppressed oncogenic KRAS expression in vitro and in vivo, associating with onset of apoptosis and loss of viability in cancer cells bearing various KRAS mutations. Collectively, our studies reveal that GRP78 is a previously unidentified regulator of oncogenic KRAS expression, and, as such, augments the other anti-cancer activities of GRP78 small molecule inhibitors to potentially achieve general, long-term suppression of mutant KRAS-driven tumorigenesis. |
| first_indexed | 2024-12-10T06:15:29Z |
| format | Article |
| id | doaj.art-e35f50ce05b445fe9d6643a6780fe18b |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-10T06:15:29Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-e35f50ce05b445fe9d6643a6780fe18b2022-12-22T01:59:28ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862022-11-0133100837Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutationsDat P. Ha0Bo Huang1Han Wang2Daisy Flores Rangel3Richard Van Krieken4Ze Liu5Soma Samanta6Nouri Neamati7Amy S. Lee8Department of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer CenterDepartment of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USADepartment of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USADepartment of Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA; USC Norris Comprehensive Cancer Center; Corresponding author at: 1441 Eastlake Avenue, Los Angeles, CA 90089.KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRASG12D-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms. Here, we report that knockdown of GRP78 via siRNA reduced oncogenic KRAS protein level in human lung, colon, and pancreatic cancer cells bearing various KRAS mutations. This effect was at the post-transcriptional level and is independent of proteasomal degradation or autophagy. Moreover, targeting GRP78 via small molecule inhibitors such as HA15 and YUM70 with anti-cancer activities while sparing normal cells significantly suppressed oncogenic KRAS expression in vitro and in vivo, associating with onset of apoptosis and loss of viability in cancer cells bearing various KRAS mutations. Collectively, our studies reveal that GRP78 is a previously unidentified regulator of oncogenic KRAS expression, and, as such, augments the other anti-cancer activities of GRP78 small molecule inhibitors to potentially achieve general, long-term suppression of mutant KRAS-driven tumorigenesis.http://www.sciencedirect.com/science/article/pii/S147655862200063XGRP78KRASLung cancerColon cancerPancreatic cancerSmall molecule inhibitors |
| spellingShingle | Dat P. Ha Bo Huang Han Wang Daisy Flores Rangel Richard Van Krieken Ze Liu Soma Samanta Nouri Neamati Amy S. Lee Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations Neoplasia: An International Journal for Oncology Research GRP78 KRAS Lung cancer Colon cancer Pancreatic cancer Small molecule inhibitors |
| title | Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations |
| title_full | Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations |
| title_fullStr | Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations |
| title_full_unstemmed | Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations |
| title_short | Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations |
| title_sort | targeting grp78 suppresses oncogenic kras protein expression and reduces viability of cancer cells bearing various kras mutations |
| topic | GRP78 KRAS Lung cancer Colon cancer Pancreatic cancer Small molecule inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S147655862200063X |
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