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

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.