KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins

Kim, Shin; Kim, Dong Eun; Kang, Hyunsu; Hong, Victor Sukbong; Jeon, Jieun; Lee, Jinho; Kim, Ki-Suk; Park, Jong-Wook

doi:10.7150/jca.85650

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J Cancer 2023; 14(12):2224-2235. doi:10.7150/jca.85650 This issue Cite

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KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins

Shin Kim^1,2,3*, Dong Eun Kim^1*, Hyunsu Kang^4,5*, Victor Sukbong Hong⁶, Jieun Jeon¹, Jinho Lee^6✉, Ki-Suk Kim^4✉, Jong-Wook Park^1,2✉

1. Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea.
2. Institute of medical science, Keimyung University, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea.
3. Institute for Cancer Research, Keimyung University, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea,
4. R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Daejeon 34114, Korea.
5. Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
6. Department of Chemistry, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, Republic of Korea.
* These authors contributed equally to this work.

✉ Corresponding authors: Jinho Lee, Ph.D. Address: Department of Chemistry, Keimyung University, 1095 Dalgubeol-daero, Daegu 42601, South Korea; Tel: +82-53-580-5183, Fax: +82-050-4154-2213, Email: jinhoac.kr. Ki-Suk Kim, Ph.D. Address: R&D C More

Citation:

Kim S, Kim DE, Kang H, Hong VS, Jeon J, Lee J, Kim KS, Park JW. KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins. J Cancer 2023; 14(12):2224-2235. doi:10.7150/jca.85650. https://www.jcancer.org/v14p2224.htm

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Abstract

The anti-proliferative effects of a newly developed N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191, have been previously evaluated in various cancer cells. However, the detailed anti-cancer molecular mechanisms of KMU-191 remain unknown. In this study, we investigated anti-cancer mechanisms by which KMU-191 regulates apoptosis-related genes in human clear cell renal cell carcinoma Caki cells. KMU-191 induced poly ADP-ribose polymerase cleavage and caspase-dependent apoptosis. In addition, KMU-191 induced down-regulation of the long form of cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the transcriptional level as well as that of long form of myeloid cell leukemia (Mcl-1 (L)) and B-cell lymphoma-extra large at the post-transcriptional level. Furthermore, KMU-191-induced apoptosis was closely associated with the Mcl-1 (L) down-regulation, but also partially associated with c-FLIP (L) down-regulation. In contrast, KMU-191 up-regulated p53, which is closely related to KMU-191-induced apoptosis. Although KMU-191 showed cytotoxicity of normal cells, it unusually did not induce cardiotoxicity. Taken together, these results suggest that a multi-target small molecule, N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191 is a potential anti-cancer agent that does not induce cardiotoxicity.

Keywords: KMU-191, Bcl-xL, Mcl-1 (L), c-FLIP (L), p53, Apoptosis, Renal cancer

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APA

Kim, S., Kim, D.E., Kang, H., Hong, V.S., Jeon, J., Lee, J., Kim, K.S., Park, J.W. (2023). KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins. Journal of Cancer, 14(12), 2224-2235. https://doi.org/10.7150/jca.85650.

ACS

Kim, S.; Kim, D.E.; Kang, H.; Hong, V.S.; Jeon, J.; Lee, J.; Kim, K.S.; Park, J.W. KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins. J. Cancer 2023, 14 (12), 2224-2235. DOI: 10.7150/jca.85650.

NLM

CSE

Kim S, Kim DE, Kang H, Hong VS, Jeon J, Lee J, Kim KS, Park JW. 2023. KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins. J Cancer. 14(12):2224-2235.

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