Interaction between HPV E6 and E7 proteins and the pregnane X receptor (PXR) in head and neck squamous cell carcinoma (HNSCC). Impact on the expression of drug metabolizing enzymes and transporters.

DYCKHOFF G; RIGALLI JP; REICHEL M; THEILE D; HEROLD-MENDE C; WEISS J

Mannheim

Congreso; EMBO Meeting 2016; 2016

EMBO

Background: HPV infection represents one of the main risk factors for HNSCC. E6and E7 are responsible for HPV oncogenic potential and can also interact with signalpathways of the host cell. PXR is a nuclear receptor related to cancer malignancy,regulated at the activity level by cofactor proteins. The aim of this work was toevaluate the modulation of PXR by HPV16- and HPV18 E6 and E7 and the effecton the expression of drug transporters and metabolizing enzymes, as typical PXRtarget genes. Observations: HPV- HNSCC cell lines HNO206 and HNO413 weretransfected with plasmids encoding E6 and E7 from HPV16, -18 or without insert(control cells). PXR activity was quantified using a plasmid encoding fireflyluciferase under the control of a PXR response element. Both cell lines showed anincrease in PXR activity by E6/E7 respect to control cells (HNO206: +48 and +52%;HNO413: +58 and +110%, for HPV16 and -18). The effect of E6/E7 transfection onthe expression of PXR, its partner RXRa, coactivators p300, SRC1, -2 and -3 andcorepressors NCoR1 and -2 was evaluated by qPCR. Results showed a significantNCoR2 down-regulation in HNO206 cells by HPV16- (-25%) and HPV18 E6/E7(-20%). HNO413 cells showed an induction of RXRa by HPV16- (+83%) andHPV18 E6/E7 (+49%). ABC drug transporters and metabolizing enzymes of theCYP450 family are known PXR target genes and thus susceptible of modulation byHPV. Indeed, qPCR showed an increase of ABCB1 (+28%) and ABCG2 (+32%) byHPV16 E6/E7 in HNO206 cells. Similarly, HPV18 E6/E7 up-regulated CYP3A4(+56%), ABCC2 (+30%) and ABCG2 (+87%) in the same cell line. HNO413 cellsshowed an induction only in ABCG2 (+22%) by HPV16 E6/E7. Conclusions: Weshowed for the first time a modulation of PXR and drug metabolizing enzymes andtransporters by HPV E6 and E7. The effect can be attributed to NCoR2down-regulation and RXRa induction. Our findings could contribute to explain thedifferent disease course associated with HPV+ HNSCC.