title: Ramalin-Mediated Apoptosis Is Enhanced by Autophagy Inhibition in Human Breast Cancer Cells.
abstract: Breast cancer, the most commonly diagnosed cancer in women worldwide, is treated in various ways. Ramalin is a chemical compound derived from the Antarctic lichen Ramalina terebrata and is known to exhibit antioxidant and antiinflammatory activities. However, its effect on breast cancer cells remains unknown. We examined the ability of ramalin to induce apoptosis and its mechanisms in MCF-7 and MDA-MB-231 human breast cancer cell lines. Ramalin inhibited cell growth and induced apoptosis in both cell lines in a concentration-dependent manner. By upregulating Bax and downregulating Bcl-2, ramalin caused cytochrome c and apoptosis-inducing factor to be released from the mitochondria into the cytosol, thus activating the mitochondrial apoptotic pathway. In addition, activated caspase-8 and caspase-9 were detected in both types of cells exposed to ramalin, whereas ramalin activated caspase-3 only in the MDA-MB-231 cells. Ramalin treatment also increased the levels of LC3-II and p62. Moreover, the inhibition of autophagy by 3-methyladenine or Atg5 siRNA significantly enhanced ramalin-induced apoptosis, which was accompanied by a decrease in Bcl-2 levels and an increase in Bax levels. Therefore, autophagy appears to be activated as a protective mechanism against apoptosis in cancer cells exposed to ramalin. These findings suggest that ramalin is a potential anticancer agent for the treatment of patients with non-invasive or invasive breast cancer.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, 440-746, Korea.
authors.forename: Eunyoung
authors.identifier: http://orcid.org/0000-0002-5474-0763
authors.initials: E
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, 440-746, Korea.
authors.forename: Chung Gi
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Polar BioCenter, Korea Polar Research Institute, KORDI, Incheon, Korea.
authors.forename: Joung-Han
authors.initials: JH
authors.lastname: Yim
authors.affiliation: Polar BioCenter, Korea Polar Research Institute, KORDI, Incheon, Korea.
authors.forename: Hong-Kum
authors.initials: HK
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, 440-746, Korea.
authors.forename: Suhkneung
authors.initials: S
authors.lastname: Pyo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D001688:Biological Products / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005971:Glutamates / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008011:Lichens / Q000737:chemistry*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D000071187:Autophagy-Related Protein 5; C494826:BAX protein, human; C000595707:BCL2 protein, human; D001688:Biological Products; D005971:Glutamates; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C570208:Ramalin; D051028:bcl-2-Associated X Protein; C025946:3-methyladenine; D045304:Cytochromes c; D020169:Caspases; D000225:Adenine
keywords: apoptosis; autophagy; breast cancer cells; ramalin