HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner

Author(s)

Rabachini, Tatiana ^[1] ; Boccardo, Enrique ^{[2, 1]} ; Andrade, Rubiana ^[2] ; Perez, Katia Regina ^{[3, 4]} ; Nonogaki, Suely ^[5] ; Cuccovia, Iolanda Midea ^[3] ; Villa, Luisa Lina ^{[6, 1]}

Affiliation

^[1] Hosp Sirio Libanes, Ludwig Inst Canc Res, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biofis, Sao Paulo, SP - Brazil

^[5] Adolfo Lutz Inst, Ctr Patol, Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: BMC CANCER; v. 18, APR 27 2018.
• Web of Science Citations: 3

Abstract

Background: Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer. HPV-16 E6 and E7 expression is essential for induction and maintenance of the transformed phenotype. These oncoproteins interfere with the function of several intracellular proteins, including those controlling the PI3K/AKT/mTOR pathway in which Phospolipase D (PLD) and Phosphatidic acid (PA) play a critical role. Methods: PLD activity was measured in primary human keratinocytes transduced with retroviruses expressing HPV-16 E6, E7 or E7 mutants. The cytostatic effect of rapamycin, a well-known mTOR inhibitor with potential clinical applications, was evaluated in monolayer and organotypic cultures. Results: HPV-16 E7 expression in primary human keratinocytes leads to an increase in PLD expression and activity. Moreover, this activation is dependent on the ability of HPV-16 E7 to induce retinoblastoma protein (pRb) degradation. We also show that cells expressing HPV-16 E7 or silenced for pRb acquire resistance to the antiproliferative effect of rapamycin. Conclusion: This is the first indication that HPV oncoproteins can affect PLD activity. Since PA can interfere with the ability of rapamycin to bind mTOR, the use of combined strategies to target mTOR and PLD activity might be considered to treat HPV-related malignancies. (AU)

• FAPESP's process: 10/20002-0 - Study of Synthetic Lethality in cells infected with Human Papillomaviruses (HPV)
• Grantee: Enrique Mario Boccardo Pierulivo
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 08/57889-1 - Institute of Science and Technology to study Diseases Associated with Papillomavirus
• Grantee: Luisa Lina Villa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 08/03232-1 - HPV and tumor microenvironment
• Grantee: Luisa Lina Villa
• Support Opportunities: Research Projects - Thematic Grants