Metabolic rewiring is associated with HPV-specific profiles in cervical cancer cell lines

Kalliopi I Pappa,Nicholas P Anagnou,George Daskalakis

doi:10.1038/s41598-021-96038-8

Abstract

Both HPV-positive and HPV-negative cervical cancers are associated with aberrant metabolism, although the oncogenic drivers remain elusive. Here we show the assessment of the metabolomic profiles of four distinct cervical cell lines, a normal and three cancer cell lines, one HPV-negative (C33A) and two HPV-positive (SiHa HPV16+, HeLa HPV18+), employing an ultra performance liquid chromatography and a high resolution mass spectrometry. Out of the total 462 metabolites, 248 to 326 exhibited statistically significant differences, while Random Forests analysis identified unique molecules for each cell line. The two HPV+ cell lines exhibited features of Warburg metabolism, consistent with the role of the HPV E6 protein. SiHa and HeLa cells displayed purine salvage pathway activity, while C33A cells revealed synthesis of cytidine, via a novel mechanism. These data document a highly dynamic HPV-specific rewiring of metabolic pathways occurring in cervical cancer. Therefore, this approach can eventually provide novel mechanistic insights into cervical carcinogenesis.

Highlights

Both Human papilloma virus (HPV)-positive and HPV-negative cervical cancers are associated with aberrant metabolism, the oncogenic drivers remain elusive
HeLa cells have been derived from a patient with cervical adenocarcinoma and contain human papilloma virus 18 (HPV-18) sequences, while p53 expression has been reported to be low with normal levels of p RB7
Cervical carcinogenesis is a multistage process following the carcinogenic infection of human papilloma virus (HPV) in virtually all cases of c ancer[6]

Summary

Introduction

Both HPV-positive and HPV-negative cervical cancers are associated with aberrant metabolism, the oncogenic drivers remain elusive. By upregulating the expression of multiple viral gene products, especially E6 and E7 oncoproteins, these high-risk HPV types, can inhibit p53 and RB tumour suppressors, respectively, which can lead to the disruption of critical cellular regulatory pathways controlling cell cycle entry, differentiation, apoptosis, cell polarity[6], and to the establishment of an aberrant cellular metabolism[5] It is of interest, that both HPV-positive and HPV-negative cervical cancers are associated with disruption of these same p athways[6,7], our current understanding of the relative contribution of these oncogenic drivers in the development and progression of cervical cancer remains incomplete[6]. HCK1T cells were recently established and immortalized from normal human cervical keratinocytes, by the introduction of the human catalytic subunit of telomerase reverse transcriptase (hTERT), and represent a reliable normal human cervical keratinocyte model, and subsequently a suitable in vitro model system for HPV-mediated multistep c arcinogenesis[8,9]

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