jsh-23 and Liver-Neoplasms

Dysregulated activation of the WNT/β-catenin signaling pathway is essential for the initiation and development of various cancers. E7386, a small-molecule compound, attenuates WNT signaling by blocking the interaction between β-catenin and CREB-binding protein (CBP); hence, it is regarded as a therapeutic candidate for cancers with activated WNT signaling. In the present study, we evaluated the biological characteristics associated with E7386 sensitivity by using a panel of patient-derived colon cancer spheroids. An integrative approach that combined E7386 sensitivity and gene expression profiles revealed that the resistance of the cancer spheroids to E7386 was associated with the activation of the NF-κB pathway. NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.

Topics: Adenocarcinoma; beta Catenin; Cell Cycle Checkpoints; Cell Proliferation; Colonic Neoplasms; CREB-Binding Protein; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; NF-kappa B; Phenylenediamines; Primary Cell Culture; Pyrazines; Spheroids, Cellular; Triazines; Wnt Signaling Pathway

The deubiquitinase otubain 2 (OTUB2) has been reported to play significant roles in the tumorigenesis of several cancers, but the role of OTUB2 in liver cancer is not investigated yet. In the present study, OTUB2 was found significantly upregulated in liver cancer tumor tissues and cell lines, and elevated OTUB2 indicated as a negative index for the overall survival of liver cancer patients. At the cellular level, knockdown of OTUB2 markedly inhibited liver cancer cell growth. Our further investigations revealed that knockdown of OTUB2 significantly suppressed NF-κB-driving luciferase activity, and markedly inhibited the phosphorylation of NF-κB p65 in liver cancer cells, which indicated that OTUB2 mediated liver cancer cell growth by regulating NF-κB signaling. Additionally, we found that liver cancer cell lines harboring higher OTUB2 expression were more sensitive to NF-κB inhibitors, and overexpression of OTUB2 could significantly reduce the antitumor effects of NF-κB inhibitors in liver cancer cells. This study indicated that OTUB2 could be a promising target for the treatment of liver cancer in the future.

Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Genes, Reporter; Hepatoblastoma; Humans; Liver Neoplasms; Luciferases; Phenyl Ethers; Phenylenediamines; Phosphorylation; Quinazolines; RNA, Small Interfering; Signal Transduction; Survival Analysis; Thiolester Hydrolases; Transcription Factor RelA