Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin

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.

Understanding and Targeting Apoptotic Pathways in Ovarian Cancer

“…The overexpression of ST6Gal1 in OVCAR4 OvCa cells that are exposed to cisplatin led to a reduction in Caspase-3 activation as measured by western blot analysis [57]. Additionally, targeting hypersialylated OvCa cells with α2, 6-linked sialic acid binding Sambucus nigra agglutinin (SNA) was shown to induce the apoptosis of IOSE-364 and SKOV3 OvCa cell lines [58]. SNA treatment was found to increase Bax and decrease Bcl-2 levels as well as increase levels of Caspase-3 and Caspase-9 as measured by western blot, to induce apoptosis [58].…”

Possible Roles of Mitochondrial Dynamics and the Effects of Pharmacological Interventions in Chemoresistant Ovarian Cancer

“…There are several studies that have shown the effects of various non-chemotherapeutic agents on mitochondrial fission in ovarian cancer. Previous reports showed that phytochemical agents including piperlongumine, piceatannol, Sambucus nigra agglutinin (SNA), and cordycepin could induce both mitochondrial fission by decreasing p-Drp1 Ser637 and increasing Drp1 and Fis1 mRNA levels, and apoptosis by decreasing anti-apoptotic Bcl-2 and increasing pro-apoptotic regulators such as Bax and Cyt C levels; and caspase activity in both chemosensitive and chemoresistant ovarian cancer cells [ 18 , 34 , 35 , 38 ]. Interestingly, these phytochemicals also enhanced the cytotoxic effects of cisplatin when combination therapy was used.…”

“…There are a limited number of studies regarding the effects of pharmacological intervention on mitochondrial fusion in ovarian cancer cell lines. Sambucus nigra agglutinin (SNA) and Cordycepin treatment led to mitochondrial dysfunction through suppressed mitochondrial fusion indicated by a decrease in expression of the fusion gene Mfn-1 and Mfn-2 in ovarian cancer cells [ 18 , 38 ]. Additionally, previous studies had indicated a correlation between nutrient stress and Bcl-2 anti-apoptotic proteins [ 42 ].…”

Lectins in Anti-Cancer Strategies

“…Растворимые лектины коммуникаций участвуют в выборе и целевой доставке ГК, причём комплексные системы приобретают широкий регулируемый спектр антиопухолевых активностей, расширяют базу востребования организмом терапевтических лектиновых комплексов. Против различных опухолей в целевых доставочных процедурах применялись фитолектины GS-I и VVA, AAL и SNA; интерлектин1 (оментин); галектин3 и галектин9 [9,11,21,27,31,34,42]. Лектины пробиотических микроорганизмов перспективны как комплексные системы целевого воздействия на мукозальный иммунитет, в том числе в противоопухолевом направлении [1,2].…”