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

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.

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

“…Autophagy analysis was performed as described previously [ 30 ]. In brief, the lentivirus packaging vectors (Pspax2, pMD2G) and GFP-LC3B/mCherry-GFP-LC3B were co-transfected into HEK293T cells using the Lipo8000 transfection reagent (C0533, Beyotime, Shanghai, China).…”

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

“…The colony formation assay was based on the previous description [ 14 ]. The cervical cancer cell HeLa was seeded onto 6-well plates at a density of 500 cells per well containing 2 mL medium.…”

Rh(III)‐Catalyzed Redox‐Neutral [4+2] Annulation for Direct Assembly of 3‐Acyl Isoquinolin‐1(2H)‐ones as Potent Antitumor Agents

“…Having established the efficient route for one‐pot synthesis of a variety of 3‐acyl isoquinolin‐1(2 H )‐ones, we next evaluated their possible bioactivities for medicinal application. Encouraged by precedent literatures on antitumor studies of isoquinolinone derivatives,– the synthesized compounds 3 a – q and 4 a – k were then evaluated against four human cancer cells, including HepG2 (human liver cancer cell line), MCF‐7 (human breast cancer cell line), A549 (human lung cancer cell line), SH‐SY5Y (human neuroblastma cell line) using CCK8 (Cell Counting Kit) assay, in which 5‐fluorouracil (5‐FU) was used as the positive control. The half‐inhibitory concentration (IC 50 ) values of all synthetic compounds were calculated and summarized in Table and Supporting Information Figure S1.…”