Function of Verticillin A in Suppression of MDSC and CRC Stem Cells

Project: Research project

Description

Project Summary The current 5-year survival rate for patients with metastatic colorectal cancer (CRC) is only about 8%.
The vast majority of CRC mortality is due to cancer cell resistance to existing therapeutic agents. Therefore,
development of novel agents that can suppress drug-resistant metastatic CRC is in urgent need. We have
purified from wild mushroom a compound with potent anti-tumor activity. This compound was identified as
Verticillin A. We demonstrated that Verticillin A modifies the BNIP3 promoter chromatin histone structure to
over-ride the silencing effect of DNA methylation to activate BNIP3 transcription in metastatic human CRC
cells. Interestingly, our preliminary studies revealed that Verticillin A is effective in suppression of drug-
resistant CRC stem cell growth. Our long-term objective is to develop Verticillin A as a therapeutic agent for
treatment of human patients with metastatic CRC. The objectives of this project are to elucidate the
underlying molecular mechanisms of Verticillin A action and to determine whether Verticillin A can
effectively suppress MDSC and drug-resistant CRC stem cells in vivo. We propose to pursue the following
three aims: 1) determine the network of DNA and H3K9 methylation in the BNIP3 promoter chromatin that
mediates BNIP transcriptional repression in human CRC cells; 2) test the hypothesis that Verticillin A
targets histone methylation to activate BNIP3 transcription and suppress spontaneous metastasis of 5-FU-
resistant CRC stem cells in vivo; and 3) test the hypothesis that Verticillin A and 5-FU cooperate to induce
MDSC apoptosis and suppress MDSC accumulation. Successful completion of these proposed studies has
the potential to develop Verticllin A as an effective drug for treatment of human patients with 5-FU-resistant
metastatic colorectal cancer.
StatusFinished
Effective start/end date1/1/1412/31/17

Funding

  • National Institutes of Health
  • National Institutes of Health

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Neoplastic Stem Cells
Colorectal Neoplasms
Fluorouracil
DNA Methylation
Pharmaceutical Preparations
Histones
Chromatin
verticillins
Myeloid-Derived Suppressor Cells
Agaricales
Methylation
Neoplasms
Therapeutics
Survival Rate
Apoptosis
Neoplasm Metastasis
Mortality

ASJC

  • Medicine(all)