PDZ-binding kinase aggravates pancreatic neuroendocrine neoplasm progression by activating the AKT/mTOR pathway.

Abstract

The therapeutic effects of existing drug regimens against pancreatic neuroendocrine neoplasms (pNENs) remain limited, and identifying ideal therapeutic targets is warranted. PDZ binding kinase (PBK) may play an oncogenic role in most solid tumors. However, its function in pNEN remains unclear. In this study, pNEN samples and International Cancer Genome Consortium data were used to determine the clinical significance of PBK. Cell counting and CCK8 assays were used to assess cell proliferation. Flow cytometry was used to assess drug-induced apoptosis and cell cycle arrest. An in vivo PBK-targeting experiment was performed in mice bearing pNENs. Western blotting, quantitative PCR, and immunohistochemistry were performed to assess the molecular mechanisms. PBK was significantly upregulated in pNEN tissues compared with paracancerous tissues. Additionally, PBK was a poor prognostic factor for pNEN patients. PBK was found to promote the proliferation of pNEN cells by activating the AKT/mTOR pathway. Furthermore, PBK inhibition combined with everolimus treatment had enhanced antitumour effects on pNEN via inhibiting AKT/mTOR pathway and inducing G0/G1 phase cell cycle arrest. This study highlights that PBK plays an oncogenic role in and is a promising therapeutic target for pNEN.

• Authors: Tingting Feng, Ruibin Jiang, Lu Yin, Chenyang Xu, Jian Ma, Wenjuan Yin, Jiaoyue Jin, Tingting Lu, Xinyuan Liu, Yingqi Lyu, Ying Yang, Lisha Ying, Qichao Hu, Dan Su, Sunbin Ling
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 62 Issue 5 Pg. 716-726 (05 2023) ISSN: 1098-2744 [Electronic] United States
• PMID: 36807309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Wiley Periodicals LLC.

Chemical References

• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Mice
• Cell Line, Tumor
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Neuroendocrine Tumors (drug therapy, genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)