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CARP-1/CCAR1: a biphasic regulator of cancer cell growth and apoptosis.

Muthu M, Cheriyan VT, Rishi AK - Oncotarget (2015)

Bottom Line: Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems.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.

View Article: PubMed Central - PubMed

Affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.

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.

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A Schematic of CARP-1/CCAR1 Apoptosis Signaling
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Figure 1: A Schematic of CARP-1/CCAR1 Apoptosis Signaling

Mentions: As mentioned earlier, CARP-1/CCAR1 was originally indentified and characterized as perinuclear phosphoprotein that was required for apoptosis signaling by chemotherapy drugs ADR and Etoposide independent of the p53 status of the HBC cells [3]. As summarized in figure 1, apoptosis induction by CARP-1/CCAR1 involves its binding with 14–3-3 protein, stimulation of CDKI p21WAF1CIP1 levels and down-regulation of cell growth and cell cycle regulators c-Myc, topoisomerase IIα, cyclin B and p21 Rac1 [3]. Genetic studies revealed that C. elegans Lst3, an ortholog of human CARP-1/CCAR1, is a transducer of Notch signaling. Lst3 also functions as an inhibitor of the EGFR-MAPK pathway [43]. These findings support our earlier studies that demonstrated CARP-1/CCAR1 requirement for apoptosis signaling following EGFR blockage in HBC cells [4]. Apoptosis signaling following EGFR inhibition invloves CARP-1/CCAR1 phosphorylation at tyrosine (Y)192, activation of the stress-activated protein kinase (SAPK) p38α/β and caspase 9 [4]. Interestingly, phosphorylation of Y189 of murine CARP-1/CCAR1 that corresponds with the Y192 of the human homolog has been noted in a global screening of p-tyrosine profile of Src-transformed MEFs [44]. It is likely that a context-dependent tyrosine phosphorylation of CARP-1/CCAR1 plays an important role in signaling for tumor growth or apoptosis, and a thorough functional characterization is needed for further understanding of the mechanism(s) involved. Pharmcologic inhibition of Protein kinase A (PKA) resulted in suppression of HBC cell growth in part by targeting CARP-1/CCAR1 threonine (T)667-dependent reduced c-Myc transcription [5]. A number of previous studies have revealed serine (S), and/or threonine (T) as well as tyrosine (Y) phosphorylation of CARP-1/CCAR1 by a variety of different signaling pathways [45–47]. CARP-1/CCAR1 was also found to be a nuclear protein in HeLa cells where it was phosphorylated at its Carboxyl terminus S1149, although the precise signaling context was not elucidated [45]. A compilation of the CARP-1/CCAR1 residues modified by phosphorylation and ubiquitination culminating from various proteomic and signaling studies thus far is available at http://www.phosphosite.org. Of note is that signaling by RIP3 kinase, oncogenic phosphatase CDC25B, Aurora and Polo-like kinases phosphorylate CARP-1/CCAR1 T627 [48–51], however, no kinase has been identified that directly phosphorylates CARP-1/CCAR1 Y192, T627, T667, or S1149.


CARP-1/CCAR1: a biphasic regulator of cancer cell growth and apoptosis.

Muthu M, Cheriyan VT, Rishi AK - Oncotarget (2015)

A Schematic of CARP-1/CCAR1 Apoptosis Signaling
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466629&req=5

Figure 1: A Schematic of CARP-1/CCAR1 Apoptosis Signaling
Mentions: As mentioned earlier, CARP-1/CCAR1 was originally indentified and characterized as perinuclear phosphoprotein that was required for apoptosis signaling by chemotherapy drugs ADR and Etoposide independent of the p53 status of the HBC cells [3]. As summarized in figure 1, apoptosis induction by CARP-1/CCAR1 involves its binding with 14–3-3 protein, stimulation of CDKI p21WAF1CIP1 levels and down-regulation of cell growth and cell cycle regulators c-Myc, topoisomerase IIα, cyclin B and p21 Rac1 [3]. Genetic studies revealed that C. elegans Lst3, an ortholog of human CARP-1/CCAR1, is a transducer of Notch signaling. Lst3 also functions as an inhibitor of the EGFR-MAPK pathway [43]. These findings support our earlier studies that demonstrated CARP-1/CCAR1 requirement for apoptosis signaling following EGFR blockage in HBC cells [4]. Apoptosis signaling following EGFR inhibition invloves CARP-1/CCAR1 phosphorylation at tyrosine (Y)192, activation of the stress-activated protein kinase (SAPK) p38α/β and caspase 9 [4]. Interestingly, phosphorylation of Y189 of murine CARP-1/CCAR1 that corresponds with the Y192 of the human homolog has been noted in a global screening of p-tyrosine profile of Src-transformed MEFs [44]. It is likely that a context-dependent tyrosine phosphorylation of CARP-1/CCAR1 plays an important role in signaling for tumor growth or apoptosis, and a thorough functional characterization is needed for further understanding of the mechanism(s) involved. Pharmcologic inhibition of Protein kinase A (PKA) resulted in suppression of HBC cell growth in part by targeting CARP-1/CCAR1 threonine (T)667-dependent reduced c-Myc transcription [5]. A number of previous studies have revealed serine (S), and/or threonine (T) as well as tyrosine (Y) phosphorylation of CARP-1/CCAR1 by a variety of different signaling pathways [45–47]. CARP-1/CCAR1 was also found to be a nuclear protein in HeLa cells where it was phosphorylated at its Carboxyl terminus S1149, although the precise signaling context was not elucidated [45]. A compilation of the CARP-1/CCAR1 residues modified by phosphorylation and ubiquitination culminating from various proteomic and signaling studies thus far is available at http://www.phosphosite.org. Of note is that signaling by RIP3 kinase, oncogenic phosphatase CDC25B, Aurora and Polo-like kinases phosphorylate CARP-1/CCAR1 T627 [48–51], however, no kinase has been identified that directly phosphorylates CARP-1/CCAR1 Y192, T627, T667, or S1149.

Bottom Line: Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems.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.

View Article: PubMed Central - PubMed

Affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.

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.

Show MeSH
Related in: MedlinePlus