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Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer

Taş, İsa LU ; Varlı, Mücahit ; Son, Yeseon ; Han, Jin ; Kwak, Dahye ; Yang, Yi ; Zhou, Rui ; Gamage, Chathurika D B ; Pulat, Sultan and Park, So-Yeon , et al. (2021) In Phytomedicine 91. p.1-13
Abstract

BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.

PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).

METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western... (More)

BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.

PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).

METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo.

RESULTS: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens.

CONCLUSION: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.

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publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Apoptosis, Breast Neoplasms/drug therapy, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Female, Glycolysis, Humans, Mice, Oxepins/pharmacology, Triple Negative Breast Neoplasms/drug therapy
in
Phytomedicine
volume
91
article number
153674
pages
1 - 13
publisher
Urban & Fischer Verlag
external identifiers
  • scopus:85111257908
  • pmid:34333327
ISSN
0944-7113
DOI
10.1016/j.phymed.2021.153674
language
English
LU publication?
no
additional info
Copyright © 2021 Elsevier GmbH. All rights reserved.
id
38c1c204-8625-473d-99ac-3c21558a26f8
date added to LUP
2022-08-25 14:29:24
date last changed
2024-06-12 16:33:06
@article{38c1c204-8625-473d-99ac-3c21558a26f8,
  abstract     = {{<p>BACKGROUND: Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action.</p><p>PURPOSE: We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC).</p><p>METHODS: The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo.</p><p>RESULTS: PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V-FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens.</p><p>CONCLUSION: The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.</p>}},
  author       = {{Taş, İsa and Varlı, Mücahit and Son, Yeseon and Han, Jin and Kwak, Dahye and Yang, Yi and Zhou, Rui and Gamage, Chathurika D B and Pulat, Sultan and Park, So-Yeon and Yu, Young Hyun and Moon, Kyung-Sub and Lee, Kyung-Hwa and Ha, Hyung-Ho and Hur, Jae-Seoun and Kim, Hangun}},
  issn         = {{0944-7113}},
  keywords     = {{Animals; Apoptosis; Breast Neoplasms/drug therapy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Female; Glycolysis; Humans; Mice; Oxepins/pharmacology; Triple Negative Breast Neoplasms/drug therapy}},
  language     = {{eng}},
  pages        = {{1--13}},
  publisher    = {{Urban & Fischer Verlag}},
  series       = {{Phytomedicine}},
  title        = {{Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer}},
  url          = {{http://dx.doi.org/10.1016/j.phymed.2021.153674}},
  doi          = {{10.1016/j.phymed.2021.153674}},
  volume       = {{91}},
  year         = {{2021}},
}