2. Academic Validation
  3. Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis

Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis

  • Cell Death Dis. 2022 Apr 23;13(4):400. doi: 10.1038/s41419-022-04828-3.
Min-Che Tung  # 1 2,  Yung-Wei Lin  # 3 4,  Wei-Jiunn Lee 3 5,  Yu-Ching Wen 3,  Yu-Cheng Liu 2,  Ji-Qing Chen 2 6,  Michael Hsiao 7,  Yi-Chieh Yang 8 9,  Ming-Hsien Chien 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Surgery, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
  • 2 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan.
  • 4 International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 6 Department of Cancer Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
  • 7 Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • 8 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 9 Department of Medical Research, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan. [email protected].
  • 10 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 11 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 12 Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 13 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 35461314 DOI: 10.1038/s41419-022-04828-3
Abstract

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies with poor prognoses, since it is largely resistant to chemotherapy, radiotherapy, and targeted therapy. The persistence of Cancer Stem Cells (CSCs) is the major cause of treatment failure with RCC. Recent evidence showed that Dopamine Receptor D2 (DRD2)-targeting antipsychotic drugs such as penfluridol exert oncostatic effects on several Cancer types, but the effect of penfluridol on RCC remains unknown. Here, we uncovered penfluridol suppressed in vitro cell growth and in vivo tumorigenicity of various RCC cell lines (Caki-1, 786-O, A498, and ACHN) and enhanced the Sutent (sunitinib)-triggered growth inhibition on clear cell (cc)RCC cell lines. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) was critical for autophagy-mediated Apoptosis induced by penfluridol. Transcriptional inhibition of OCT4 and Nanog via inhibiting GLI1 was important for penfluridol-induced stemness and proliferation inhibition. The Anticancer activities of penfluridol on ccRCC partially occurred through DRD2. In clinical ccRCC specimens, positive correlations of DRD2 with GLI1, OCT4, and Nanog were observed and their expressions were correlated with worse prognoses. Summarizing, DRD2 antagonists such as penfluridol induce UPR signaling and suppress the GLI1/OCT4/Nanog axis in ccRCC cells to reduce their growth through inducing autophagy-mediated Apoptosis and stemness inhibition. These drugs can be repurposed as potential agents to treat ccRCC patients.

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