Mechanisms of neuroblastoma cell growth inhibition by CARP-1 functional mimetics

Our plain-English summary of Mechanisms of neuroblastoma cell growth inhibition by CARP-1 functional mimetics, by M. Muthu, V.T. Cheriyan, S. Munie, et al (PloS One, 2014).

The study

• Authors: M. Muthu, V.T. Cheriyan, S. Munie, E. Levi, J. Frank, A.E. Ashour, M. Singh, A.K. Rishi
• Journal: PloS One
• Published: 2014;9(7):e102567
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Neuroblastomas (NBs) are a clinically heterogeneous group of extra cranial pediatric tumors. Patients with high-risk, metastatic NBs have a long-term survival rate of below 40%, and are often resistant to current therapeutic modalities. Due to toxic side effects associated with radiation and chemotherapies, development of new agents is warranted to overcome resistance and effectively treat this disease in clinic. CARP-1 functional mimetics (CFMs) are an emerging class of small molecule compounds that inhibit growth of diverse cancer cell types. Here we investigated NB inhibitory potential of CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited NB cell growth, in vitro, independent of their p53 and MYCN status. CFM-4 and -5 induced apoptosis in NB cells in part by activating pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, stimulating CARP-1 expression and cleavage of PARP1, while promoting loss of the oncogenes C and N-myc as well as mitotic cyclin B1. Treatments of NB cells with CFM-4 or -5 also resulted in loss of Inhibitory κB (IκB) α and β proteins. Micro-RNA profiling revealed upregulation of XIAP-targeting miR513a-3p in CFM-4-treated NB, mesothelioma, and breast cancer cells. Moreover, exposure of NB and breast cancer cells to CFM-4 or -5 resulted in diminished expression of anti-apoptotic XIAP1, cIAP1, and Survivin proteins. Expression of anti-miR513a-5p or miR513a-5p mimic, however, interfered with or enhanced, respectively, the breast cancer cell growth inhibition by CFM-4. CFMs also impacted biological properties of the NB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Our studies indicate anti-NB properties of CFM-4 and 5, and suggest that these CFMs and/or their future analogs have potential as anti-NB agents.

In plain English

This was a laboratory study of cancer cells grown in dishes. It involved no patients and did not study asbestos. The authors tested experimental compounds called CARP-1 functional mimetics (CFM-1, CFM-4 and CFM-5) on four human neuroblastoma cell lines (neuroblastoma is a childhood cancer). They compared the compounds with the chemotherapy drug Adriamycin (ADR). Over 24 hours, the highest tested dose of CFM-4 or CFM-5 reduced the viability of the SK-N-SH and SK-N-BE(2) neuroblastoma lines by about 70–80%. A high dose of CFM-1 and one ADR dose reduced it by about 30–33%. CFM-4 and CFM-5 caused signs of programmed cell death (apoptosis). They also lowered the MYCN and c-Myc proteins and reduced the cell-survival proteins XIAP1, cIAP1 and survivin. In a microRNA profiling experiment, CFM-4 raised levels of three small RNA molecules, including miR-513a-5p, in neuroblastoma, breast cancer and malignant pleural mesothelioma (H2373) cells. The compounds also reduced the neuroblastoma cells' ability to migrate, form colonies and invade through a gel-coated membrane. The authors concluded that CFM-4 and CFM-5 have potential as anti-neuroblastoma agents.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture experiment, described by the authors as a proof-of-concept study
• Who was studied: Four human neuroblastoma cell lines (SK-N-AS, SK-N-DZ, SK-N-BE(2), SK-N-SH), with most mechanism experiments in SK-N-SH and SK-N-BE(2). The study also used human breast cancer cells (MDA-MB-468, MDA-MB-231) and malignant pleural mesothelioma H2373 cells. No human subjects.
• Exposure: Experimental small-molecule compounds CFM-1, CFM-4 and CFM-5, compared with the chemotherapy drug Adriamycin (ADR). Not an asbestos exposure study.
• Main results:
  • In SK-N-SH and SK-N-BE(2) neuroblastoma cells, a 24-hour treatment with the 20 (printed 'mM') dose of CFM-4 or CFM-5 caused about 70–80% loss of viability.
  • In the same two neuroblastoma lines, the 20 dose of CFM-1 and the 1 dose of ADR each caused about 30–33% loss of viability.
  • Over 48 hours at the 5 dose, CFM-4 or CFM-5 reduced neuroblastoma cell viability by about 70–80%. Breast cancer cells showed only moderate to minimal loss of viability.
  • CFM treatment increased the number of neuroblastoma cells showing DNA fragmentation, a marker of apoptosis.
  • CFM-4 and CFM-5 reduced MYCN protein in both neuroblastoma lines. ADR did not reduce MYCN in either line.
  • CFM-4 raised levels of the microRNAs miR-513a-5p, miR-1290 and miR-1973 in breast cancer, neuroblastoma and malignant pleural mesothelioma cells.
  • CFM-4 or CFM-5 depleted the cell-survival proteins XIAP1, cIAP1 and survivin in both neuroblastoma lines.
  • CFM-4 or CFM-5 significantly reduced the number of neuroblastoma cells able to invade through matrigel-coated membranes.
  • In SK-N-SH cells, CFM-4 or CFM-5 caused a moderate but significant loss of MMP-9 activity only, among the enzymes measured.
• The authors' conclusion: The authors concluded that their studies indicate anti-neuroblastoma properties of CFM-4 and CFM-5, and that these compounds or future analogs have potential as anti-neuroblastoma agents.
• Limitations the authors state:
  • The authors stated it remains unclear whether the NF-kB activation caused by CFMs contributes to cell death or instead helps some cells survive.
  • The authors stated that further studies are needed to clarify whether raised miR-1290 contributes to growth inhibition.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma.

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