Inhibition of C-terminal truncated PPM1D enhances the effect of doxorubicin on cell viability in human colorectal carcinoma cell line |
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| Institution: | 1. Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan;2. Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan;1. Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK;2. Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;3. Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;4. Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;1. Shenzhen University Cancer Research Center, Institute of Otorhinolaryngology, Shenzhen 518060, China;2. Sun Yat-sen University Cancer Center, Guangzhou 510060, China;1. Department of Chemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia;2. Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora 3086, Australia;3. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA;1. Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India;2. Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India;3. Analytical Chemistry-Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India |
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| Abstract: | PPM1D is a p53-inducible Ser/Thr phosphatase. One of the main functions of PPM1D in normal cells is to act as a negative regulator of the p53 tumor suppressor by dephosphorylating p53 and several kinases. PPM1D is considered an oncoprotein owing to both its functions and the fact that gene amplification and overexpression of PPM1D are reported in several tumors. Recently, PPM1D mutations resulting in C-terminal truncated alterations were found in brainstem gliomas and colorectal cancers, and these mutations enhanced the activity of PPM1D. Therefore, C-terminal truncated PPM1D should be also considered as a potential candidate target of anticancer drugs. Here we showed that combination treatment with PPM1D-specific inhibitor SPI-001 and doxorubicin suppressed cell viability of HCT-116 cells overexpressing C-terminal truncated PPM1D through p53 activation compared with doxorubicin alone. Our results suggest that combination treatment with PPM1D inhibitor and doxorubicin may be a potential anti-cancer treatment in PPM1D-mutated cancer cells. |
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| Keywords: | Inhibitor Phosphatase Cell cycle Cancer Combination effect |
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