Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3

Feiyan Liu, Qianqian Liu, Dafeng Yang, Wendy B. Bollag, Keith D Robertson, Ping Wu, Kebin Liu

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Drug resistance is a major cause of failure in cancer chemotherapy. Therefore, identification and combined use of adjuvant compounds that can overcome drug resistance may improve the efficacy of cancer therapy. We screened extracts of Verticillium species-infected mushrooms for antitumor compounds and identified the compound Verticillin A as an inducer of hepatoma cell apoptosis in vitro and an inhibitor of tumor xenograft growth in vivo. Verticillin A exhibited a potent apoptosis-sensitizing activity in human colon carcinoma cells exposed to TRAIL or Fas in vitro. Furthermore, Verticillin A effectively sensitized metastatic human colon carcinoma xenograft to TRAIL-mediated growth inhibition in vivo. At the molecular level, we observed that Verticillin A induces cell-cycle arrest in the G 2 phase of the cell cycle in human colon carcinoma cells, markedly upregulating BNIP3 in both hepatoma and colon carcinoma cells. Notably, silencing BNIP3 decreased the sensitivity of tumor cells to Verticillin A-induced apoptosis in the absence or presence of TRAIL. We found that the BNIP3 promoter is methylated in both human hepatoma and colon carcinoma cells and tumor specimens. Verticillin A upregulated the expression of a panel of genes known to be regulated at the level of DNA methylation, in support of the concept that Verticillin A may act by demethylating the BNIP3 promoter to upregulate BNIP3 expression. Taken together, our findings identify Verticillin A as a potent apoptosis sensitizer with great promise for further development as an adjuvant agent to overcome drug resistance in human cancer therapy.

Original languageEnglish (US)
Pages (from-to)6807-6816
Number of pages10
JournalCancer Research
Volume71
Issue number21
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

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DNA Methylation
Colon
Up-Regulation
Apoptosis
Carcinoma
Drug Resistance
Hepatocellular Carcinoma
Neoplasms
Heterografts
Verticillium
verticillins
Agaricales
Growth
Helper-Inducer T-Lymphocytes
Cell Cycle Checkpoints
Human Activities
Cell Cycle
Drug Therapy
Therapeutics
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3. / Liu, Feiyan; Liu, Qianqian; Yang, Dafeng; Bollag, Wendy B.; Robertson, Keith D; Wu, Ping; Liu, Kebin.

In: Cancer Research, Vol. 71, No. 21, 01.11.2011, p. 6807-6816.

Research output: Contribution to journalArticle

Liu, Feiyan ; Liu, Qianqian ; Yang, Dafeng ; Bollag, Wendy B. ; Robertson, Keith D ; Wu, Ping ; Liu, Kebin. / Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3. In: Cancer Research. 2011 ; Vol. 71, No. 21. pp. 6807-6816.
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