title: Inhibition of C-terminal truncated PPM1D enhances the effect of doxorubicin on cell viability in human colorectal carcinoma cell line.
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.
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kozakai
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Kamada
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kiyota
authors.affiliation: Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanino
authors.affiliation: Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan. Electronic address: kazuyasu@sci.hokudai.ac.jp.
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010616:Phenanthrenes; C573895:SPI-001; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: Cancer; Cell cycle; Combination effect; Inhibitor; Phosphatase