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Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin.
- Source :
-
Cell death & disease [Cell Death Dis] 2017 May 04; Vol. 8 (5), pp. e2762. Date of Electronic Publication: 2017 May 04. - Publication Year :
- 2017
-
Abstract
- Ovarian carcinoma (OC) patients encounter the severe challenge of clinical management owing to lack of screening measures, chemoresistance and finally dearth of non-toxic therapeutics. Cancer cells deploy various defense strategies to sustain the tumor microenvironment, among which deregulated apoptosis remains a versatile promoter of cancer progression. Although recent research has focused on identifying agents capable of inducing apoptosis in cancer cells, yet molecules efficiently breaching their survival advantage are yet to be classified. Here we identify lectin, Sambucus nigra agglutinin (SNA) to exhibit selectivity towards identifying OC by virtue of its specific recognition of α-2, 6-linked sialic acids. Superficial binding of SNA to the OC cells confirm the hyper-sialylated status of the disease. Further, SNA activates the signaling pathways of AKT and ERK1/2, which eventually promotes de-phosphorylation of dynamin-related protein-1 (Drp-1). Upon its translocation to the mitochondrial fission loci Drp-1 mediates the central role of switch in the mitochondrial phenotype to attain fragmented morphology. We confirmed mitochondrial outer membrane permeabilization resulting in ROS generation and cytochrome-c release into the cytosol. SNA response resulted in an allied shift of the bioenergetics profile from Warburg phenotype to elevated mitochondrial oxidative phosphorylation, altogether highlighting the involvement of mitochondrial dysfunction in restraining cancer progression. Inability to replenish the SNA-induced energy crunch of the proliferating cancer cells on the event of perturbed respiratory outcome resulted in cell cycle arrest before G2/M phase. Our findings position SNA at a crucial juncture where it proves to be a promising candidate for impeding progression of OC. Altogether we unveil the novel aspect of identifying natural molecules harboring the inherent capability of targeting mitochondrial structural dynamics, to hold the future for developing non-toxic therapeutics for treating OC.
- Subjects :
- Cell Survival drug effects
Cytochromes c metabolism
Cytosol metabolism
Dynamins
Female
GTP Phosphohydrolases metabolism
Humans
Membrane Potential, Mitochondrial drug effects
Microscopy, Confocal
Microtubule-Associated Proteins metabolism
Mitochondrial Proteins metabolism
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Ovarian Neoplasms metabolism
Ovarian Neoplasms pathology
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt metabolism
Reactive Oxygen Species metabolism
S Phase Cell Cycle Checkpoints drug effects
Signal Transduction drug effects
Apoptosis drug effects
Mitochondria metabolism
Mitochondrial Dynamics drug effects
Plant Lectins pharmacology
Ribosome Inactivating Proteins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 8
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 28471452
- Full Text :
- https://doi.org/10.1038/cddis.2017.77