Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma

• Published in: Oncotarget Vol. 8; no. 68; pp. 112610 - 112622
• Main Authors: Yoon, Ji-Yong, Lee, Jeong-Ju, Gu, Sujin, Jung, Myoung Eun, Cho, Hyun-Soo, Lim, Jung Hwa, Jun, Soo Young, Ahn, Jun-Ho, Min, Ju-Sik, Choi, Min-Hyuk, Jeon, Su-Jin, Lee, Yong-Jae, Go, Areum, Heo, Yun-Jeong, Jung, Cho-Rok, Choi, Gildon, Lee, Kwangho, Jeon, Moon-Kook, Kim, Nam-Soon
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 22.12.2017
• Subjects: Research Paper; HCC; apoptosis; TRAIL sensitizer; TIPRL
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22614

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). , injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC.