Abstract
BackgroundHuman 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.MethodsPLD 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.ResultsHPV-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.ConclusionThis 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.
Highlights
Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer
HPV-16 E7 expression increases Phospolipase D (PLD) protein expression and activity PLD1 and PLD2 catalyze the hydrolysis of phosphatidylcholine (PC) to phosphatidic acid (PA) and choline [23]
Our results show that primary human keratinocytes (PHK), expressing HPV-16 E6 and E7 or E7 alone, show an increase in both PLD1 and PLD2 isoforms when compared with keratinocytes transduced only with the empty vector (Fig. 1a)
Summary
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. Phospholipase D enzymes play a fundamental role in cells: they maintain the integrity of cellular membranes and they participate in cell signaling including cytoskeletal dynamics, cell migration, intracellular protein trafficking, and cell proliferation. Consistent with this data, increased PLD activity has been reported in a large number of human cancers, including breast, colon, gastric, and kidney [20]
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