title: CARP-1/CCAR1: a biphasic regulator of cancer cell growth and apoptosis.
abstract: Targeted cancer therapy using small molecule inhibitors (SMIs) has been useful in targeting the tumor cells while sparing the normal cells. Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems. Thus, there is an urgent need to identify targets to devise new means to treat cancers and their drug-resistant phenotypes. CARP-1/CCAR1 (Cell division cycle and apoptosis regulator 1), a peri-nuclear phospho-protein, plays a dynamic role in regulating cell growth and apoptosis by serving as a co-activator of steroid/thyroid nuclear receptors, β-catenin, Anaphase Promoting Complex/Cyclosome (APC/C) E3 ligase, and tumor suppressor p53. CARP-1/CCAR1 also regulates chemotherapy-dependent apoptosis. CARP-1/CCAR1 functional mimetics (CFMs) are a novel SMIs of CARP-1/CCAR1 interaction with APC/C. CFMs promote apoptosis in a manner independent of p53. CFMs are potent inhibitors of a variety of cancer cells including the drug (Adriamycin or Tamoxifen)-resistant breast cancer cells but not the immortalized breast epithelial cells, while a nano-lipid formulation of the lead compound CFM-4 improves its bioavailability and efficacy in vivo when administered orally. This review focuses on the background and pleiotropic roles of CARP-1/CCAR1 as well as its apoptosis signaling mechanisms in response to chemotherapy in cancer cells.
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.|Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Magesh
authors.initials: M
authors.lastname: Muthu
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.|Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Vino T
authors.initials: VT
authors.lastname: Cheriyan
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.|Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.|Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000627:therapeutic use; D013830:Thiadiazoles / Q000627:therapeutic use
chemical_list: C569107:1-(2-chlorobenzyl)-5'-phenyl-3'H-spiro(indoline-3,2'-(1,3,4)thiadiazol)-2-one; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; D013141:Spiro Compounds; D013830:Thiadiazoles
keywords: CARP-1/CCAR1; CFMs; apoptosis