Restoring apoptosis in breast cancer via peptide mediated disruption of survivin IAP interaction
Seyedeh Marzieh Taghavifar1, Saba Sabbaghfarshi1, Hamidreza Samadikhah2,3
1Institute of Biosocial and Quantum Science and Technologies, CT.C, Islamic Azad University, Tehran, Iran.
Abstract:
Apoptosis is a form of programmed cell death mediated by caspases and regulated through both intrinsic and extrinsic pathways. Many cancers evade apoptosis, resulting in uncontrolled cell survival and tumor progression. Inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP1, cIAP2, ML-IAP (also known as Livin), Survivin, NAIP, ILP-2, and BRUCE (also known as Apollon), play crucial roles in suppressing apoptosis and promoting cancer cell survival. Survivin, which is overexpressed in various malignancies, inhibits caspase activity, protects XIAP from proteasomal degradation, and suppresses the intrinsic apoptotic pathway by inhibiting caspase-9 activity. In this study, we investigated the protective role of Survivin on other IAPs, particularly NAIP and cIAP1, using bioinformatics approaches such as homology modeling, molecular docking, and molecular dynamics simulations. Experimental validation in MCF-7 breast cancer cells demonstrated that a novel anticancer peptide, P3, disrupts the interaction between Survivin and IAPs. At 25 µM, P3 significantly enhanced caspase-8 and -9 (initiator) and caspases-3 and -7 (executioner) activities, activating pathways. These effects were confirmed by flow cytometry and DAPI/PI staining, showing increased apoptosis without necrosis. Our findings indicate P3 as a promising peptide-based therapy to overcome apoptosis resistance in breast cancer by targeting Survivin-IAP complexes, providing a foundation for novel anticancer strategies.
Insights
A novel peptide, P3, effectively targets Survivin-inhibitor of apoptosis protein (IAP) complexes. This disruption reactivates programmed cell death pathways, offering a promising strategy to combat apoptosis resistance in breast cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer cells often evade apoptosis, a programmed cell death process, leading to tumor progression.
- Inhibitor of Apoptosis Proteins (IAPs), such as Survivin, are crucial in suppressing apoptosis and promoting cancer cell survival.
- Survivin overexpression in malignancies hinders caspase activity and the intrinsic apoptotic pathway.
Purpose of the Study:
- To investigate Survivin's protective role on other IAPs (NAIP, cIAP1) using computational methods.
- To evaluate a novel peptide (P3) for its ability to disrupt Survivin-IAP interactions.
- To assess P3's efficacy in inducing apoptosis in breast cancer cells.
Main Methods:
- Bioinformatics approaches including homology modeling, molecular docking, and molecular dynamics simulations.
- Experimental validation using MCF-7 breast cancer cells.
- Assays for caspase activity, flow cytometry, and DAPI/PI staining to measure apoptosis.
Main Results:
- Bioinformatics analysis elucidated Survivin's interactions with NAIP and cIAP1.
- The peptide P3 was found to disrupt the Survivin-IAP complex.
- P3 treatment significantly increased initiator (caspase-8, -9) and executioner (caspase-3, -7) activities, inducing apoptosis without necrosis.
Conclusions:
- The peptide P3 effectively targets Survivin-IAP complexes, overcoming apoptosis resistance in breast cancer.
- P3 demonstrates potential as a novel peptide-based therapeutic agent for cancer treatment.
- This study provides a foundation for developing new anticancer strategies targeting IAP interactions.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:17The Extrinsic Apoptotic Pathway
01:30Apoptosis
01:20The JAK-STAT Signaling Pathway
02:23Abnormal Proliferation
02:34Inhibition of Cdk Activity