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

Cho,Jung  Jae; Chae,Jung-Il; Kim,Ka  Hwi; Cho,Jin  Hyoung; Jeon,Young-Joo; Oh,Ha  Na; Yoon,Goo; Yoon,Do  Young; Cho,Young  Sik; Cho,Seung-Sik; Shim,Jung-Hyun

doi:10.3892/ijo.2015.3151

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

Authors:
- Jung Jae Cho
- Jung-Il Chae
- Ka Hwi Kim
- Jin Hyoung Cho
- Young-Joo Jeon
- Ha Na Oh
- Goo Yoon
- Do Young Yoon
- Young Sik Cho
- Seung-Sik Cho
- Jung-Hyun Shim
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Affiliations: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea, Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, BK21 plus, Chonbuk National University, Jeonju 651-756, Republic of Korea, Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea, College of Pharmacy, Keimyung University, 1000 Sindang-dong, Dalseo-gu, Daegu 704-701, Republic of Korea
Published online on: September 8, 2015 https://doi.org/10.3892/ijo.2015.3151
Pages: 1954-1962

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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.

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