Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer
Abstract Gemcitabine (GEM) is the standard chemotherapy drug for pancreatic cancer. Because of widespread drug resistance, the effect is limited. Therefore, it is urgent to reveal the underlying mechanism. Glycolysis is the most remarkable character of tumor aberrant metabolism, which plays vital ro...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-10-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.2463 |
| _version_ | 1819118484314914816 |
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| author | Kun Fan Zhiyao Fan He Cheng Qiuyi Huang Chao Yang Kaizhou Jin Guopei Luo Xianjun Yu Chen Liu |
| author_facet | Kun Fan Zhiyao Fan He Cheng Qiuyi Huang Chao Yang Kaizhou Jin Guopei Luo Xianjun Yu Chen Liu |
| author_sort | Kun Fan |
| collection | DOAJ |
| description | Abstract Gemcitabine (GEM) is the standard chemotherapy drug for pancreatic cancer. Because of widespread drug resistance, the effect is limited. Therefore, it is urgent to reveal the underlying mechanism. Glycolysis is the most remarkable character of tumor aberrant metabolism, which plays vital roles on tumor drug resistance. Hexokinase 2 (HK2), as the key enzyme regulating the first‐step reaction of glycolysis, is overexpressed in many kinds of tumors. The putative role of HK2 resisting GEM therapy was investigated in this study. We found that HK2 was overexpressed in pancreatic cancer and associated with poor prognosis. HK2 knockdown decreased pancreatic cancer cell proliferation, migration viability, and promoted cell apoptosis in vitro. HK2 high expression in pancreatic cancer showed GEM resistance. HK2 knockdown increased the sensitivity of pancreatic cancer cell to GEM, the growth of xenograft tumor with HK2 knockdown was also further decreased with the GEM treatment compared with control in vivo. GEM‐resistant pancreatic cancer showed the increase of HK2 dimer rather than HK2 mRNA or protein. Our study revealed that the ROS derived from GEM promoted HK2 dimerization combining with voltage‐dependent anion channel, which resulted in the resistance to GEM. Meanwhile, our study established a new sight for GEM resistance in pancreatic cancer. |
| first_indexed | 2024-12-22T05:49:36Z |
| format | Article |
| id | doaj.art-34a2f127293e4649a4686c8fa3ee246a |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-12-22T05:49:36Z |
| publishDate | 2019-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-34a2f127293e4649a4686c8fa3ee246a2022-12-21T18:36:55ZengWileyCancer Medicine2045-76342019-10-018135903591510.1002/cam4.2463Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancerKun Fan0Zhiyao Fan1He Cheng2Qiuyi Huang3Chao Yang4Kaizhou Jin5Guopei Luo6Xianjun Yu7Chen Liu8Department of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaDepartment of Pancreatic Surgery Fudan University Shanghai Cancer Center Shanghai P.R. ChinaAbstract Gemcitabine (GEM) is the standard chemotherapy drug for pancreatic cancer. Because of widespread drug resistance, the effect is limited. Therefore, it is urgent to reveal the underlying mechanism. Glycolysis is the most remarkable character of tumor aberrant metabolism, which plays vital roles on tumor drug resistance. Hexokinase 2 (HK2), as the key enzyme regulating the first‐step reaction of glycolysis, is overexpressed in many kinds of tumors. The putative role of HK2 resisting GEM therapy was investigated in this study. We found that HK2 was overexpressed in pancreatic cancer and associated with poor prognosis. HK2 knockdown decreased pancreatic cancer cell proliferation, migration viability, and promoted cell apoptosis in vitro. HK2 high expression in pancreatic cancer showed GEM resistance. HK2 knockdown increased the sensitivity of pancreatic cancer cell to GEM, the growth of xenograft tumor with HK2 knockdown was also further decreased with the GEM treatment compared with control in vivo. GEM‐resistant pancreatic cancer showed the increase of HK2 dimer rather than HK2 mRNA or protein. Our study revealed that the ROS derived from GEM promoted HK2 dimerization combining with voltage‐dependent anion channel, which resulted in the resistance to GEM. Meanwhile, our study established a new sight for GEM resistance in pancreatic cancer.https://doi.org/10.1002/cam4.2463GEM resistanceHK2 dimerpancreatic cancerROSVDAC |
| spellingShingle | Kun Fan Zhiyao Fan He Cheng Qiuyi Huang Chao Yang Kaizhou Jin Guopei Luo Xianjun Yu Chen Liu Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer Cancer Medicine GEM resistance HK2 dimer pancreatic cancer ROS VDAC |
| title | Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| title_full | Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| title_fullStr | Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| title_full_unstemmed | Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| title_short | Hexokinase 2 dimerization and interaction with voltage‐dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| title_sort | hexokinase 2 dimerization and interaction with voltage dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer |
| topic | GEM resistance HK2 dimer pancreatic cancer ROS VDAC |
| url | https://doi.org/10.1002/cam4.2463 |
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