Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway

Our plain-English summary of Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway, by K.H. Kim, J.I. Chae, H. Oh, et al (Oncology Reports, 2016).

The study

• Authors: K.H. Kim, J.I. Chae, H. Oh, J.H. Cho, R.H. Lee, G. Yoon, S.S. Cho, Y.S. Cho, M.H. Lee, K. Liu, H.J. Lee, J.H. Shim
• Journal: Oncology Reports
• Published: 2016;36(1):117-24
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Manumycin A (Manu A) is a natural product isolated from Streptomyces parvulus and has been reported to have anti-carcinogenic and anti-biotic properties. However, neither its molecular mechanism nor its molecular targets are well understood. Thus, the aim of the present study was to explore the possibility that Manu A has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. Manu A inhibited the cell viability of MSTO-211H and H28 cells in a concentration‑dependent manner as determined by MTS assay. IC50 values were calculated as 8.3 and 4.3 µM in the MSTO-311H and H28 cells following 48 h incubation, respectively. Manu A induced a significant increase in apoptotic indices as shown by DAPI staining, Annexin V assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by Manu A led to apoptosis by suppressing Sp1-regulated proteins (cyclin D1, Mcl-1 and survivin). Manu A decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. Manu A caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that Manu A exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.

In plain English

This laboratory study tested manumycin A, a natural compound from the bacterium Streptomyces parvulus, on two human malignant pleural mesothelioma cell lines, MSTO-211H and H28. The cells were treated with 2.5, 5 and 10 µM of the compound for 24 or 48 hours. After 48 hours, the concentration that halved cell viability (IC50) was 8.3 µM for MSTO-211H cells and 4.3 µM for H28 cells. After 48 hours, across the tested range of 0 to 10 µM, the share of cells undergoing apoptosis (programmed cell death) rose from 11.15% to 95.80% in MSTO-211H cells and from 0.93% to 90.25% in H28 cells. Treated cells had lower levels of the protein Sp1 and of the Sp1-regulated proteins cyclin D1, Mcl-1 and survivin. They also showed more depolarized mitochondria, higher caspase activity, more of the proteins CHOP, DR4, DR5 and Bax, and less PARP. The authors concluded that manumycin A lowered Sp1, which in turn led to cell death through both the intrinsic and the extrinsic pathways. The work used only cells grown in the laboratory. It did not study asbestos exposure, animals or patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro laboratory experiment on human cancer cell lines
• Who was studied: Two commercially obtained human malignant pleural mesothelioma cell lines, MSTO-211H and H28; no patients or animals
• Exposure: Manumycin A, a compound purified from Streptomyces, at 2.5, 5 and 10 µM for 24 and 48 hours. Asbestos was not part of the experiments.
• Main results:
  • After 48 hours of incubation, the IC50 of manumycin A was 8.3 µM in MSTO-211H cells and 4.3 µM in H28 cells. The article's abstract prints the first cell line as MSTO-311H; the Results name it MSTO-211H.
  • After 48 hours across the 0 to 10 µM range, the total apoptotic cell population increased from 11.15% to 95.80% in MSTO-211H cells and from 0.93% to 90.25% in H28 cells
  • Sp1 mRNA levels fell with increasing dose in both cell lines
  • Sp1 target proteins (cyclin D1, Mcl-1, survivin) were reduced after 48 hours in both cell lines
  • Cells with depolarized mitochondria at increasing doses: 38.7%, 51.9% and 72.1% in MSTO-211H cells; 2.73%, 86.0% and 93.9% in H28 cells
  • Total multi-caspase activity at increasing doses: 23.7%, 43.3% and 62.2% in MSTO-211H cells; 15.8%, 19.0% and 78.9% in H28 cells
  • CHOP, DR4 and DR5 protein levels increased in both cell lines
  • Bax protein increased with dose
  • PARP decreased in both cell lines
• The authors' conclusion: The authors concluded that manumycin A lowered Sp1 protein levels, which in turn induced apoptosis of the mesothelioma cells through both the intrinsic and the extrinsic pathways, and that it is promising as an anticancer agent.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Pleural Mesothelioma, Carcinogenic.

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• Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation — Y.J. Lee, Y.J. Lee, et al. (2015)
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• Phosphatidylinositol Induces Caspase-Independent Apoptosis of Malignant Pleural Mesothelioma Cells by Accumulating AIF in the Nucleus — S. Kanemura, A. Tsuchiya, et al. (2015)
• Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma — I. Mohiuddin, X. Cao, et al. (2001)

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