Abstract
Cancer remains one of the biggest threats to human society. There are massive demands for compounds to selectively kill cancerous cells. Earlier studies have shown that bovine α -lactalbumin made lethal to tumor cells (BAMLET) becomes cytotoxic against cancer cells in complex with oleic acid {Hoque, M. et. al., PLoSOne8, e68390 (2013)}. In our study, we obtained bovine α-lactalbumin complexed with lanthanum ion (La3+-B-α-LA) and determined its high resolution crystal structure. The natural calcium binding site of bovine α-lactalbumin is replaced by lanthanum. The La3+ complex formation by B-α-apo-LA was also supported by various biophysical methods. Interestingly, our complex, La3+-B-α-LA exhibits much greater anticancer activity against breast cancer cells as compared to the reported BAMLET-oleic acid complex. This study shows that La3+-B-α-LA complex is preferentially more toxic to MCF-7 cells as compared to KB (oral cancer) and HeLa (cervical) cells, while almost non-toxic to the healthy cells that we studied. Our data indicates that the cytotoxicity of La3+-B-α-LA against cancer cells is through apoptotic path way. The higher anticancer activity of La3+-B-α-LA is attributable to the requisite structural changes induced in the protein by La3+ binding as supported by the crystal structure of the complex.
Highlights
IntroductionWe obtained bovine α-lactalbumin complexed with lanthanum ion (La3+-B-α-LA) and determined its high resolution crystal structure
The fluorescence emission spectra were recorded upon addition of La3+ to apo-bovine α-lactalbumin (B-α-LA) at λex = 295 nm and only a maximum of ~20% quenching was observed (Fig. 1b), supporting that the La3+ binding to protein does not substantially alter the structure where the aromatic side chains are present
The integrated green fluorescence intensity is >3 times higher when the MCF-7 cells were treated with La3+-B-α-LA complex as compared to the same when treated with simple La3+ salt (Fig. 8p). Both the absorption and emission spectra clearly showed the interaction of La3+ with apo-B-α-LA, and ICP-AES and the Isothermal titration calorimetry (ITC) showed 1:1 protein: La3+ complex
Summary
We obtained bovine α-lactalbumin complexed with lanthanum ion (La3+-B-α-LA) and determined its high resolution crystal structure. The higher anticancer activity of La3+-B-α-LA is attributable to the requisite structural changes induced in the protein by La3+ binding as supported by the crystal structure of the complex. Conversion of native α-lactalbumin into the apoptosis inducing form, BAMLET/HAMLET, involves partial unfolding of the protein followed by complexing with oleic acid followed by stabilising the partially folded conformation[8,9,10,11,12,13,14,15,16,17]. Some recent studies report the binding of B-α-LA to nanoclusters[19,20] and nanoparticles[21] of gold Such nano-species show alternative pathways for stabilizing the unfolded state of B-α-LA so that the resulting protein-metal nano-composites express their required properties[22]. The details of apoptosis were probed in one case, and the activity was compared with that reported in the literature
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