Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma
Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim...
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| Format: | Article |
| Language: | English |
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BMC
2021-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-021-01912-y |
| _version_ | 1831636744593735680 |
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| author | Sanghwa Kim Minji Lee Yeonhwa Song Su-Yeon Lee Inhee Choi I-Seul Park Jiho Kim Jin-sun Kim Kang mo Kim Haeng Ran Seo |
| author_facet | Sanghwa Kim Minji Lee Yeonhwa Song Su-Yeon Lee Inhee Choi I-Seul Park Jiho Kim Jin-sun Kim Kang mo Kim Haeng Ran Seo |
| author_sort | Sanghwa Kim |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim to new targets for HCC drug discovery using HCC tumor spheroids. Methods Our comparative proteomic analysis of HCC cells grown in culture as monolayers (2D) and spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression was higher in 3D cells than in 2D cells due to upregulated endoplasmic reticulum (ER) stress responses. We investigated the clinical value of ASS1 in Korean patients with HCC. The mechanism underlying ASS1-mediated tumor suppression was investigated in HCC spheroids. ASS1-mediated improvement of chemotherapy efficiency was observed using high content screening in an HCC xenograft mouse model. Results Studies of tumor tissue from Korean HCC patients showed that, although ASS1 expression was low in most samples, high levels of ASS1 were associated with favorable overall survival of patients. Here, we found that bidirectional interactions between ASS1 ER stress responses in HCC-derived multicellular tumor spheroids can limit HCC progression. ASS1 overexpression effectively inhibited tumor growth and enhanced the efficacy of in vitro and in vivo anti-HCC combination chemotherapy via activation of the PERK/eIF2α/ATF4/CHOP axis, but was not dependent on the status of p53 and arginine metabolism. Conclusions These results demonstrate the critical functional roles for the arginine metabolism–independent tumor suppressor activity of ASS1 in HCC and suggest that upregulating ASS1 in these tumors is a potential strategy in HCC cells with low ASS1 expression. |
| first_indexed | 2024-12-19T06:38:47Z |
| format | Article |
| id | doaj.art-e5f2ab7eaab24620b6335ddbce5e7714 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-19T06:38:47Z |
| publishDate | 2021-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e5f2ab7eaab24620b6335ddbce5e77142022-12-21T20:32:10ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-04-0140111810.1186/s13046-021-01912-yArgininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinomaSanghwa Kim0Minji Lee1Yeonhwa Song2Su-Yeon Lee3Inhee Choi4I-Seul Park5Jiho Kim6Jin-sun Kim7Kang mo Kim8Haeng Ran Seo9Cancer Biology Research Laboratory, Institut Pasteur KoreaCancer Biology Research Laboratory, Institut Pasteur KoreaCancer Biology Research Laboratory, Institut Pasteur KoreaCancer Biology Research Laboratory, Institut Pasteur KoreaMedicinal Chemistry, Institut Pasteur KoreaScreening Discovery Platform, Institut Pasteur KoreaScreening Discovery Platform, Institut Pasteur KoreaDepartment of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of MedicineDepartment of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of MedicineCancer Biology Research Laboratory, Institut Pasteur KoreaAbstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim to new targets for HCC drug discovery using HCC tumor spheroids. Methods Our comparative proteomic analysis of HCC cells grown in culture as monolayers (2D) and spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression was higher in 3D cells than in 2D cells due to upregulated endoplasmic reticulum (ER) stress responses. We investigated the clinical value of ASS1 in Korean patients with HCC. The mechanism underlying ASS1-mediated tumor suppression was investigated in HCC spheroids. ASS1-mediated improvement of chemotherapy efficiency was observed using high content screening in an HCC xenograft mouse model. Results Studies of tumor tissue from Korean HCC patients showed that, although ASS1 expression was low in most samples, high levels of ASS1 were associated with favorable overall survival of patients. Here, we found that bidirectional interactions between ASS1 ER stress responses in HCC-derived multicellular tumor spheroids can limit HCC progression. ASS1 overexpression effectively inhibited tumor growth and enhanced the efficacy of in vitro and in vivo anti-HCC combination chemotherapy via activation of the PERK/eIF2α/ATF4/CHOP axis, but was not dependent on the status of p53 and arginine metabolism. Conclusions These results demonstrate the critical functional roles for the arginine metabolism–independent tumor suppressor activity of ASS1 in HCC and suggest that upregulating ASS1 in these tumors is a potential strategy in HCC cells with low ASS1 expression.https://doi.org/10.1186/s13046-021-01912-yHepatocellular carcinoma (HCC)Argininosuccinate synthase 1(ASS1)Endoplasmic reticulum (ER) stressSpheroidsC/EBP homologous protein (CHOP) |
| spellingShingle | Sanghwa Kim Minji Lee Yeonhwa Song Su-Yeon Lee Inhee Choi I-Seul Park Jiho Kim Jin-sun Kim Kang mo Kim Haeng Ran Seo Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research Hepatocellular carcinoma (HCC) Argininosuccinate synthase 1(ASS1) Endoplasmic reticulum (ER) stress Spheroids C/EBP homologous protein (CHOP) |
| title | Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma |
| title_full | Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma |
| title_fullStr | Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma |
| title_full_unstemmed | Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma |
| title_short | Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma |
| title_sort | argininosuccinate synthase 1 suppresses tumor progression through activation of perk eif2α atf4 chop axis in hepatocellular carcinoma |
| topic | Hepatocellular carcinoma (HCC) Argininosuccinate synthase 1(ASS1) Endoplasmic reticulum (ER) stress Spheroids C/EBP homologous protein (CHOP) |
| url | https://doi.org/10.1186/s13046-021-01912-y |
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