Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. Approximately 15% of GC is associated with Epstein−Barr virus (EBV). GC is largely incurable with a dismal five-year survival rate. There is an urgent need to identify new therape...
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| Format: | Article |
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MDPI AG
2020-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/2/365 |
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| author | Xiangyu Ke Qingsong Qin Tianyi Deng Yueyan Liao Shou-Jiang Gao |
| author_facet | Xiangyu Ke Qingsong Qin Tianyi Deng Yueyan Liao Shou-Jiang Gao |
| author_sort | Xiangyu Ke |
| collection | DOAJ |
| description | Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. Approximately 15% of GC is associated with Epstein−Barr virus (EBV). GC is largely incurable with a dismal five-year survival rate. There is an urgent need to identify new therapeutic agents for the treatment of GC. Tenovin-6 was initially identified as a p53 activator, but it was later found to inhibit autophagy flux, and the protein deacetylase activity of sirtuins. Tenovin-6 shows promising therapeutic effect in various malignancies. However, it remains unknown whether Tenovin-6 is effective for GC. In this study, we found that EBV-positive and -negative GC cell lines were sensitive to Tenovin-6 but with different response times and doses. Tenovin-6 suppressed anchorage-independent growth of GC cells. Tenovin-6 induced different levels of apoptosis and phases of cell-cycle arrest depending on the cell lines with some manifesting gap 1 (G1) and others showing synthesis (S) phase cell-cycle arrest. Mechanistically, Tenovin-6 induced autophagy or p53 activation in GC cells depending on the status of <i>TP53</i> gene. However, initiation of autophagy following treatment with Tenovin-6 conferred some protective effect on numerous cells. Combined treatment with Tenovin-6 and autophagy inhibitor chloroquine increased the cytotoxic effect by inducing microtubule-associated protein 1 light chain 3B (LC3B)-II accumulation, and by enhancing apoptosis and cell-cycle arrest. These results indicated that Tenovin-6 can be used as a potential therapeutic agent for GC, but the genetic background of the cancer cells might determine the response and mechanism of action. Treatment with Tenovin-6 alone or in combination with chloroquine could be a promising therapeutic approach for GC. |
| first_indexed | 2024-03-12T08:02:28Z |
| format | Article |
| id | doaj.art-f5e27f72ca17428cbcb6747031d94a6f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:02:28Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f5e27f72ca17428cbcb6747031d94a6f2023-09-02T19:48:41ZengMDPI AGCancers2072-66942020-02-0112236510.3390/cancers12020365cancers12020365Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with ChloroquineXiangyu Ke0Qingsong Qin1Tianyi Deng2Yueyan Liao3Shou-Jiang Gao4Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou 515000, ChinaLaboratory of Human Virology and Oncology, Shantou University Medical College, Shantou 515000, ChinaLaboratory of Human Virology and Oncology, Shantou University Medical College, Shantou 515000, ChinaLaboratory of Human Virology and Oncology, Shantou University Medical College, Shantou 515000, ChinaUPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USAGastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. Approximately 15% of GC is associated with Epstein−Barr virus (EBV). GC is largely incurable with a dismal five-year survival rate. There is an urgent need to identify new therapeutic agents for the treatment of GC. Tenovin-6 was initially identified as a p53 activator, but it was later found to inhibit autophagy flux, and the protein deacetylase activity of sirtuins. Tenovin-6 shows promising therapeutic effect in various malignancies. However, it remains unknown whether Tenovin-6 is effective for GC. In this study, we found that EBV-positive and -negative GC cell lines were sensitive to Tenovin-6 but with different response times and doses. Tenovin-6 suppressed anchorage-independent growth of GC cells. Tenovin-6 induced different levels of apoptosis and phases of cell-cycle arrest depending on the cell lines with some manifesting gap 1 (G1) and others showing synthesis (S) phase cell-cycle arrest. Mechanistically, Tenovin-6 induced autophagy or p53 activation in GC cells depending on the status of <i>TP53</i> gene. However, initiation of autophagy following treatment with Tenovin-6 conferred some protective effect on numerous cells. Combined treatment with Tenovin-6 and autophagy inhibitor chloroquine increased the cytotoxic effect by inducing microtubule-associated protein 1 light chain 3B (LC3B)-II accumulation, and by enhancing apoptosis and cell-cycle arrest. These results indicated that Tenovin-6 can be used as a potential therapeutic agent for GC, but the genetic background of the cancer cells might determine the response and mechanism of action. Treatment with Tenovin-6 alone or in combination with chloroquine could be a promising therapeutic approach for GC.https://www.mdpi.com/2072-6694/12/2/365gastric cancerepstein–barr virus (ebv)tenovin-6chloroquineautophagyp53 activation |
| spellingShingle | Xiangyu Ke Qingsong Qin Tianyi Deng Yueyan Liao Shou-Jiang Gao Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine Cancers gastric cancer epstein–barr virus (ebv) tenovin-6 chloroquine autophagy p53 activation |
| title | Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine |
| title_full | Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine |
| title_fullStr | Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine |
| title_full_unstemmed | Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine |
| title_short | Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine |
| title_sort | heterogeneous responses of gastric cancer cell lines to tenovin 6 and synergistic effect with chloroquine |
| topic | gastric cancer epstein–barr virus (ebv) tenovin-6 chloroquine autophagy p53 activation |
| url | https://www.mdpi.com/2072-6694/12/2/365 |
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