Manumycin A from a new Streptomyces strain induces endoplasmic reticulum stress-mediated cell death through specificity protein 1 signaling in human oral squamous cell carcinoma

Int J Oncol. 2015 Nov;47(5):1954-62. doi: 10.3892/ijo.2015.3151. Epub 2015 Sep 8.

Abstract

Manumycin A (Manu A) is a natural antibiotic produced by new Streptomyces strain, exhibiting antitumor and anticancer effects. However, the anticancer effects of Manu A on oral squamous cell carcinoma (OSCC) have not been reported. OSCC is an aggressive type of cancer because of its poor prognosis and low survival rate despite advanced medical treatment. We observed that Manu A reduced cell growth and Sp1 protein levels in OSCC cell lines (HN22 and HSC4) in a dose- and time-dependent manner. We also observed downregulation of Sp1 downstream target genes such as p27, p21, Mcl-1 and survivin. Moreover, nuclear staining with DAPI showed that Manu A was able to cause nuclear condensation and further fragmentation. Flow cytometry analyses using Annexin V and propiodium iodide supported Manu A-mediated apoptotic cell death of OSCC cells. Furthermore, Bcl-2 family such as mitochondrial pro‑apoptotic Bax, anti-apoptotic Bcl-xl and Bid were regulated by Manu A, triggering the mitochondrial apoptotic pathway. In conclusion, these results indicate that Manu A is a potential to treat human OSCC via cell apoptosis through the downregulation of Sp1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / pathology
  • Neoplasm Proteins / biosynthesis
  • Polyenes / administration & dosage*
  • Polyenes / chemistry
  • Polyunsaturated Alkamides / administration & dosage*
  • Polyunsaturated Alkamides / chemistry
  • Signal Transduction / drug effects
  • Sp1 Transcription Factor / biosynthesis*
  • Sp1 Transcription Factor / genetics
  • Streptomyces / chemistry

Substances

  • Neoplasm Proteins
  • Polyenes
  • Polyunsaturated Alkamides
  • Sp1 Transcription Factor
  • manumycin