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Abstract
Introduction Cervical cancer is the most common malignancy among women caused due to persistent high-risk human papillomavirus (HR-HPV) infection. The carcinogenesis of HPV is attributed to its early viral onco-proteins E6/E7, which increase cellular proliferation and survival mechanisms by interacting with cellular survival pathways including AKT/mTOR kinases, and activator protein-1 (AP-1; Jun/Fos) and E2F transcription factors. Cervical cancer cells become addicted to E6/E7 expression and undergo apoptosis when E6/E7 are disrupted. Previously, we demonstrated functional synergism between the HSP70-inhibitor SHetA2 and the CDK4/6-inhibitor palbociclib in cervical cancer. However, this synergism’s mechanism was not explored with respect to targeting HPV E6/E7 onco-proteins. Hence, the objective of this study was to evaluate the impact of SHetA2 and palbociclib alone, and in combination, on HPV E6/E7 and associated survival pathways.
Methods Individual or combination treatments of SHetA2 and palbociclib in HR-HPV positive cervical cancer cell lines were evaluated for specific mRNA and protein modulation by western blotting, quantitative polymerase chain reaction (qPCR) and immunofluorescence.
Results We demonstrated for the first time that combination treatment of SHetA2 and palbociclib causes significant down-regulation of E6/E7 viral proteins and up-regulation of c-Jun and c-Fos host proteins (figure 1). The effects of the combination treatment were greater than either single treatment. Consistent with the down-regulation of E6/E7, SHetA2 impacted AKT/mTOR phosphorylation.
Conclusion/Implications This study identifies potential anti-HPV preventative and therapeutic strategies using combination therapy of SHetA2 and palbociclib. Future research will study SHetA2 and/or palbociclib mechanisms in pre-clinical models and conduct clinical trials of HR-HPV-driven pre-cancerous lesions.
