Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromos...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06313-x |
| _version_ | 1827602717119348736 |
|---|---|
| author | Saimeng Shi Duancheng Guo Longyun Ye Tianjiao Li Qinglin Fei Mengxiong Lin Xianjun Yu Kaizhou Jin Weiding Wu |
| author_facet | Saimeng Shi Duancheng Guo Longyun Ye Tianjiao Li Qinglin Fei Mengxiong Lin Xianjun Yu Kaizhou Jin Weiding Wu |
| author_sort | Saimeng Shi |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC. |
| first_indexed | 2024-03-09T05:24:29Z |
| format | Article |
| id | doaj.art-9a85e684f5cb4e558f07329aad902170 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-09T05:24:29Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9a85e684f5cb4e558f07329aad9021702023-12-03T12:38:10ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111810.1038/s41419-023-06313-xKnockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancerSaimeng Shi0Duancheng Guo1Longyun Ye2Tianjiao Li3Qinglin Fei4Mengxiong Lin5Xianjun Yu6Kaizhou Jin7Weiding Wu8Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterAbstract Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.https://doi.org/10.1038/s41419-023-06313-x |
| spellingShingle | Saimeng Shi Duancheng Guo Longyun Ye Tianjiao Li Qinglin Fei Mengxiong Lin Xianjun Yu Kaizhou Jin Weiding Wu Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer Cell Death and Disease |
| title | Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| title_full | Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| title_fullStr | Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| title_full_unstemmed | Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| title_short | Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| title_sort | knockdown of tacc3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer |
| url | https://doi.org/10.1038/s41419-023-06313-x |
| work_keys_str_mv | AT saimengshi knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT duanchengguo knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT longyunye knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT tianjiaoli knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT qinglinfei knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT mengxionglin knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT xianjunyu knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT kaizhoujin knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer AT weidingwu knockdownoftacc3inhibitstumorcellproliferationandincreaseschemosensitivityinpancreaticcancer |