Tong-Hong Wang1, Chin-Chuan Chen2, Yann-Lii Leu2, Yun-Shien Lee3, Jang-Hau Lian4, Hsi-Lung Hsieh5, Chi-Yuan Chen6. 1. Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan; Graduate Institute of Health Industry Technology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan 33303, Taiwan; Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan. 2. Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan; Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan 33303, Taiwan. 3. Department of Biotechnology, Ming Chuan University, 5 De Ming Rd., Taoyuan City 333, Taiwan; Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan. 4. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan. 5. Graduate Institute of Health Industry Technology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan 33303, Taiwan; Department of Neurology, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan. Electronic address: hlhsieh@mail.cgust.edu.tw. 6. Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan; Graduate Institute of Health Industry Technology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan 33303, Taiwan. Electronic address: d49417002@gmail.com.
Abstract
BACKGROUND/ PURPOSE: Palbociclib is an FDA-approved cyclin-dependent kinase (CDK) 4/6 inhibitor that has been clinically proven to be effective in breast cancer. However, its use in oral cancer is not well researched. In this study, we investigated the inhibitory activity of palbociclib against oral squamous cell carcinoma (OSCC) cells and explored the mechanism of inhibition. METHODS: The effects of palbociclib on the cytotoxicity of OSCC cells were determined by MTT and colony formation assays. β-Galactosidase staining and cell-cycle analysis were used to determine palbociclib-induced cellular senescence and apoptosis of OSCC cells. Wound healing and transwell assays were performed to assess the effects of palbociclib treatment on migration and invasion ability of OSCC cells. Whole transcriptome sequencing was conducted to show the relationship between DNA damage repair of OSCC cells and palbociclib treatment. Palbociclib-induced DNA damage and repair capacity of OSCC cells were confirmed by comet assay and immunofluorescence confocal microscopy. Western blotting was used to verify the palbociclib-mediated changes in the CDK/pRB/c-Myc/CDC25A pathway. Finally, in vitro findings were tested in a mouse xenograft model. RESULTS: Our results showed that palbociclib can significantly inhibit the growth, migration, and invasive ability of OSCC cells and can accelerate cellular senescence and apoptosis. We found that palbociclib induced DNA damage and p21 expression through the p53-independent pathway, thereby downregulating c-Myc and CDC25A expression to inhibit cell cycle progression. In addition, palbociclib downregulated RAD51 expression to inhibit DNA damage repair ability of OSCC cell. CONCLUSION: Palbociclib was found to have anti-oral squamous cell carcinoma activity and to simultaneously induce DNA damage and inhibit its repair, and to accelerated cellular senescence and apoptosis.
BACKGROUND/ PURPOSE:Palbociclib is an FDA-approved cyclin-dependent kinase (CDK) 4/6 inhibitor that has been clinically proven to be effective in breast cancer. However, its use in oral cancer is not well researched. In this study, we investigated the inhibitory activity of palbociclib against oral squamous cell carcinoma (OSCC) cells and explored the mechanism of inhibition. METHODS: The effects of palbociclib on the cytotoxicity of OSCC cells were determined by MTT and colony formation assays. β-Galactosidase staining and cell-cycle analysis were used to determine palbociclib-induced cellular senescence and apoptosis of OSCC cells. Wound healing and transwell assays were performed to assess the effects of palbociclib treatment on migration and invasion ability of OSCC cells. Whole transcriptome sequencing was conducted to show the relationship between DNA damage repair of OSCC cells and palbociclib treatment. Palbociclib-induced DNA damage and repair capacity of OSCC cells were confirmed by comet assay and immunofluorescence confocal microscopy. Western blotting was used to verify the palbociclib-mediated changes in the CDK/pRB/c-Myc/CDC25A pathway. Finally, in vitro findings were tested in a mouse xenograft model. RESULTS: Our results showed that palbociclib can significantly inhibit the growth, migration, and invasive ability of OSCC cells and can accelerate cellular senescence and apoptosis. We found that palbociclib induced DNA damage and p21 expression through the p53-independent pathway, thereby downregulating c-Myc and CDC25A expression to inhibit cell cycle progression. In addition, palbociclib downregulated RAD51 expression to inhibit DNA damage repair ability of OSCC cell. CONCLUSION:Palbociclib was found to have anti-oral squamous cell carcinoma activity and to simultaneously induce DNA damage and inhibit its repair, and to accelerated cellular senescence and apoptosis.
Authors: Andrea M Pesch; Nicole H Hirsh; Anna R Michmerhuizen; Kassidy M Jungles; Kari Wilder-Romans; Benjamin C Chandler; Meilan Liu; Lynn M Lerner; Charles A Nino; Connor Ward; Erin F Cobain; Theodore S Lawrence; Lori J Pierce; James M Rae; Corey W Speers Journal: JCI Insight Date: 2022-02-08