PMID- 37033362 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231116 IS - 2219-6803 (Electronic) IS - 2218-676X (Print) IS - 2218-676X (Linking) VI - 12 IP - 3 DP - 2023 Mar 31 TI - PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling. PG - 461-472 LID - 10.21037/tcr-22-2272 [doi] AB - BACKGROUND: P21-activated kinase 4 (PAK4) involves in cell proliferation in cancer and mutually regulates with p53, a molecule is demonstrated to control cell autophagy by mammalian target of rapamycin (mTOR)/protein kinase B (AKT) signaling. Since the signaling exhibits an association with PAK family members in cell autophagy, it implies that PAK4-relevant proliferation may be impacted by autophagy via p53 with a lack of evidence in cancer cells. METHODS: In this research, transient and stable PAK4-knockdown human hepatocarcinoma cell lines (HepG2) were constructed by transfection of PAK4-RNA interference (RNAi) plasmid and lentivirus containing PAK4-RNAi plasmid, respectively. We investigated cell proliferation using methyl thiazolyl tetrazolium (MTT) and Cell Counting Kit 8 (CCK8) assays, cell cycle by flow cytometry (FCM) and cell autophagy by monodansylcadaverine (MDC) staining and autophagic biomarker's expression, and detected the expressions of p53, mTOR, phosphorylated-AKT (p-AKT) and AKT by immunofluorescence and western blot to explore the mechanism. RESULTS: We successfully constructed transient and stable PAK4-knockdown HepG2 cell lines, and detected dysfunction of the cells' proliferation. An increased expression of p53, as a molecule of cell-cycle-surveillance on G1/S phase, was demonstrated in the cells although the cell cycle blocked at G2/M. And then, we detected increased autophagosome and autophagic biomarker LC3-II, and decreased expressions in p-AKT and mTOR. CONCLUSIONS: The proliferation is reduced in PAK4-knockdown HepG2 cells, which is relative to not only cell cycle arrest but also cell autophagy, and p53/mTOR/p-AKT signaling involves in the cell progress. The findings provide a new mechanism on PAK4 block in cancer therapy. CI - 2023 Translational Cancer Research. All rights reserved. FAU - Li, Qing AU - Li Q AD - Institute of Pathophysiology, College of Basic Medical Sciences, Lanzhou University, Lanzhou, China. FAU - Wang, Su-Jie AU - Wang SJ AD - Institute of Pathophysiology, College of Basic Medical Sciences, Lanzhou University, Lanzhou, China. FAU - Wang, Wen-Jia AU - Wang WJ AD - Clinical Laboratory, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, China. FAU - Ye, Yu-Cai AU - Ye YC AD - Institute of Pathophysiology, College of Basic Medical Sciences, Lanzhou University, Lanzhou, China. FAU - Ling, Ya-Qin AU - Ling YQ AD - Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, Beijing, China. FAU - Dai, Ya-Fei AU - Dai YF AD - Institute of Pathophysiology, College of Basic Medical Sciences, Lanzhou University, Lanzhou, China. LA - eng PT - Journal Article DEP - 20230321 PL - China TA - Transl Cancer Res JT - Translational cancer research JID - 101585958 EIN - Transl Cancer Res. 2023 Oct 31;12(10):2968-2969. PMID: 37969396 PMC - PMC10080326 OTO - NOTNLM OT - P21-activated kinase 4 (PAK4) OT - autophagy OT - cell cycle OT - mammalian target of rapamycin (mTOR) OT - p53 COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2272/coif). The authors have no conflicts of interest to declare. EDAT- 2023/04/11 06:00 MHDA- 2023/04/11 06:01 PMCR- 2023/03/31 CRDT- 2023/04/10 03:52 PHST- 2022/09/23 00:00 [received] PHST- 2023/02/19 00:00 [accepted] PHST- 2023/04/11 06:01 [medline] PHST- 2023/04/10 03:52 [entrez] PHST- 2023/04/11 06:00 [pubmed] PHST- 2023/03/31 00:00 [pmc-release] AID - tcr-12-03-461 [pii] AID - 10.21037/tcr-22-2272 [doi] PST - ppublish SO - Transl Cancer Res. 2023 Mar 31;12(3):461-472. doi: 10.21037/tcr-22-2272. Epub 2023 Mar 21.