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

Magesh Muthu^1,2, Vino T Cheriyan^1,2, Arun K Rishi^1,3,2

¹John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.

|April 21, 2015

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.

Insights

Novel small molecule inhibitors (SMIs), CARP-1/CCAR1 functional mimetics (CFMs), effectively target cancer cells, including drug-resistant phenotypes, by inducing apoptosis independently of p53.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Targeted cancer therapies using small molecule inhibitors (SMIs) face challenges like off-target effects and drug resistance.
Cell division cycle and apoptosis regulator 1 (CARP-1/CCAR1) is a key protein regulating cell growth, apoptosis, and chemotherapy response.
There is a critical need for novel therapeutic targets to overcome cancer drug resistance.

Purpose of the Study:

To review the roles of CARP-1/CCAR1 in cancer.
To explore the mechanisms of CARP-1/CCAR1-mediated apoptosis in response to chemotherapy.
To introduce CARP-1/CCAR1 functional mimetics (CFMs) as novel SMIs targeting cancer.

Main Methods:

Review of existing literature on CARP-1/CCAR1 function and its role in cancer.
Analysis of CARP-1/CCAR1 interaction with the Anaphase Promoting Complex/Cyclosome (APC/C).
Evaluation of CFMs as inhibitors of cancer cell proliferation and in drug-resistant models.

Main Results:

CARP-1/CCAR1 acts as a co-activator for various nuclear receptors and proteins involved in cell cycle and apoptosis.
CFMs are novel SMIs that inhibit CARP-1/CCAR1 interaction with APC/C, inducing apoptosis independently of p53.
CFMs demonstrate potent inhibition of diverse cancer cells, including Adriamycin- or Tamoxifen-resistant breast cancer cells, without affecting normal breast epithelial cells.
A nano-lipid formulation of CFM-4 enhances its oral bioavailability and in vivo efficacy.

Conclusions:

CARP-1/CCAR1 plays a multifaceted role in cancer cell regulation and apoptosis.
CFMs represent a promising new class of SMIs for treating various cancers, including drug-resistant types.
Further research into CARP-1/CCAR1 and CFMs could lead to improved cancer therapies.

Read full analysis

Keywords:

CARP-1/CCAR1 CFMs apoptosis

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