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Targeting HSP70-E7 Interaction With SHetA2: A Novel Therapeutic Strategy for Cervical Cancer
Justin Garland1, Showket Hussain2,3, Rajani Rai3
1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Abstract:
Cervical cancer is predominantly driven by persistent infections with high-risk human papillomavirus and the continuous activity of its E6 and E7 oncoproteins. This study explored the role of heat shock proteins 70 kDa (HSP70s) in enhancing the function of these oncoproteins and examined the impact of SHetA2, an investigational new drug, on this interaction. We found that HSP70 specifically binds to E7, but not E6, protein and that SHetA2 disrupts this binding. This disruption led to a significant reduction in E6 and E7 mRNA and E7 protein levels, while effects on E6 protein levels were minimal. SHetA2 treatment also resulted in altered levels of cell cycle regulatory proteins, reduced cell cycle progression, and decreased metabolic viability in cervical cancer cell lines and xenograft models. These findings support the potential of SHetA2 to impair cervical cancer progression by targeting HSP70/E7 interactions, highlighting its promise as a therapeutic strategy for treating cervical cancer.
Insights
SHetA2 drug disrupts heat shock protein 70 (HSP70) binding to the E7 oncoprotein, reducing cervical cancer cell growth. This targeted approach shows promise for treating human papillomavirus-driven cervical cancers.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Cervical cancer is primarily caused by persistent high-risk human papillomavirus (HPV) infections.
- The HPV E6 and E7 oncoproteins are crucial for cancer development and progression.
- Heat shock proteins 70 kDa (HSP70s) may enhance the function of these oncoproteins.
Purpose of the Study:
- To investigate the interaction between HSP70 and HPV oncoproteins (E6 and E7).
- To evaluate the effect of SHetA2, an investigational drug, on the HSP70/oncoprotein interaction.
- To assess the therapeutic potential of SHetA2 in cervical cancer models.
Main Methods:
- Assessed HSP70 binding specificity to E6 and E7 oncoproteins.
- Investigated the impact of SHetA2 on HSP70/E7 binding.
- Quantified E6 and E7 mRNA and protein levels after SHetA2 treatment.
- Analyzed cell cycle regulatory proteins, cell cycle progression, and metabolic viability in vitro and in vivo.
Main Results:
- HSP70 specifically binds to the E7 oncoprotein, not E6.
- SHetA2 effectively disrupts the HSP70/E7 interaction.
- SHetA2 treatment significantly reduces E6 and E7 mRNA and E7 protein levels.
- SHetA2 alters cell cycle regulators, inhibits cell cycle progression, and decreases metabolic viability in cervical cancer cells and xenografts.
Conclusions:
- Targeting the HSP70/E7 interaction with SHetA2 impairs cervical cancer progression.
- SHetA2 demonstrates therapeutic potential for cervical cancer treatment.
- The findings support SHetA2 as a promising strategy against HPV-driven cervical malignancies.
