A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Jul 31

PMID 31357480

Citations 6

Authors

He-Ying Chen

Liu-Jun He

Shi-Qiang Li

Ya-Jun Zhang

Jiu-Hong Huang

Hong-Xia Qin

Juan-Li Wang

Qian-Yin Li

Dong-Lin Yang

Affiliations

Soon will be listed here.

Abstract

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.

Citing Articles

Benzimidazole scaffold as a potent anticancer agent with different mechanisms of action (2016-2023).

Hagar F, Abbas S, Atef E, Abdelhamid D, Abdel-Aziz M Mol Divers. 2024; 29(2):1821-1849.

PMID: 39031290 DOI: 10.1007/s11030-024-10907-8.

Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF-α-Amino Carboxylates.

Vorobyeva D, Petropavlovskikh D, Godovikov I, Dolgushin F, Osipov S Molecules. 2022; 27(23).

PMID: 36500580 PMC: 9736582. DOI: 10.3390/molecules27238488.

A novel 3-acyl isoquinolin-1(2H)-one induces G2 phase arrest, apoptosis and GSDME-dependent pyroptosis in breast cancer.

Ma L, Bian M, Gao H, Zhou Z, Yi W PLoS One. 2022; 17(5):e0268060.

PMID: 35551332 PMC: 9098002. DOI: 10.1371/journal.pone.0268060.

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

Yang D, Zhang Y, He L, Hu C, Gao L, Huang J Biol Res. 2021; 54(1):27.

PMID: 34488902 PMC: 8420005. DOI: 10.1186/s40659-021-00350-6.

A Novel Imidazopyridine Derivative Exerts Anticancer Activity by Inducing Mitochondrial Pathway-Mediated Apoptosis.

Wang J, Wu H, Song G, Yang D, Huang J, Yao X Biomed Res Int. 2020; 2020:4929053.

PMID: 32908894 PMC: 7468608. DOI: 10.1155/2020/4929053.

References

Kawaguchi Y, Kovacs J, McLaurin A, Vance J, Ito A, Yao T . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003; 115(6):727-38. DOI: 10.1016/s0092-8674(03)00939-5. View

Kurland J, Tansey W . Crashing waves of destruction: the cell cycle and APC(Cdh1) regulation of SCF(Skp2). Cancer Cell. 2004; 5(4):305-6. DOI: 10.1016/s1535-6108(04)00091-1. View

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

Zhang L, Wang C . F-box protein Skp2: a novel transcriptional target of E2F. Oncogene. 2005; 25(18):2615-27. PMC: 1513044. DOI: 10.1038/sj.onc.1209286. View

Salon C, Merdzhanova G, Brambilla C, Brambilla E, Gazzeri S, Eymin B . E2F-1, Skp2 and cyclin E oncoproteins are upregulated and directly correlated in high-grade neuroendocrine lung tumors. Oncogene. 2007; 26(48):6927-36. DOI: 10.1038/sj.onc.1210499. View

Reichert M, Saur D, Hamacher R, Schmid R, Schneider G . Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res. 2007; 67(9):4149-56. DOI: 10.1158/0008-5472.CAN-06-4484. View

Sathornsumetee S, Reardon D, Desjardins A, Quinn J, Vredenburgh J, Rich J . Molecularly targeted therapy for malignant glioma. Cancer. 2007; 110(1):13-24. DOI: 10.1002/cncr.22741. View

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View

Chu I, Hengst L, Slingerland J . The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008; 8(4):253-67. DOI: 10.1038/nrc2347. View

10.

Wen P, Kesari S . Malignant gliomas in adults. N Engl J Med. 2008; 359(5):492-507. DOI: 10.1056/NEJMra0708126. View

11.

Lee J, Koga H, Kawaguchi Y, Tang W, Wong E, Gao Y . HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 2010; 29(5):969-80. PMC: 2837169. DOI: 10.1038/emboj.2009.405. View

12.

Mizushima N, Yoshimori T, Levine B . Methods in mammalian autophagy research. Cell. 2010; 140(3):313-26. PMC: 2852113. DOI: 10.1016/j.cell.2010.01.028. View

13.

Wang H, Cui J, Bauzon F, Zhu L . A comparison between Skp2 and FOXO1 for their cytoplasmic localization by Akt1. Cell Cycle. 2010; 9(5):1021-2. PMC: 2990537. DOI: 10.4161/cc.9.5.10916. View

14.

Yeh C, So M, Ng J, Yang H, Chang M, Lai M . Hepatitis B virus-DNA level and basal core promoter A1762T/G1764A mutation in liver tissue independently predict postoperative survival in hepatocellular carcinoma. Hepatology. 2010; 52(6):1922-33. DOI: 10.1002/hep.23898. View

15.

Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q . STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal. 2013; 25(4):931-8. DOI: 10.1016/j.cellsig.2013.01.011. View

16.

Chan C, Morrow J, Zhang S, Lin H . Skp2: a dream target in the coming age of cancer therapy. Cell Cycle. 2014; 13(5):679-80. PMC: 3979895. DOI: 10.4161/cc.27853. View

17.

Lu Z, Bauzon F, Fu H, Cui J, Zhao H, Nakayama K . Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity. Nat Commun. 2014; 5:3463. PMC: 3982150. DOI: 10.1038/ncomms4463. View

18.

Wang Z, Liu P, Inuzuka H, Wei W . Roles of F-box proteins in cancer. Nat Rev Cancer. 2014; 14(4):233-47. PMC: 4306233. DOI: 10.1038/nrc3700. View

19.

Hao Z, Huang S . E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. Front Biosci (Landmark Ed). 2015; 20(3):474-90. DOI: 10.2741/4320. View

20.

Lu W, Liu S, Li B, Xie Y, Adhiambo C, Yang Q . SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget. 2015; 6(2):771-88. PMC: 4359254. DOI: 10.18632/oncotarget.2718. View