Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation.

Redox Biol

Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China; Department of Urology, The First Hospital of Jilin University, Changchun, 130021, China; School of Life Sciences, Henan University, Kaifeng, 475000, China. Electronic address:

Published: May 2024

AI Article Synopsis

  • High-risk HPVs, particularly HPV16, are linked to cervical cancer by promoting cell growth through the activation of the pentose phosphate pathway (PPP).
  • The HPV16 E6 protein enhances the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) by preventing its lactylation, which in turn supports tumor growth in cervical cancer cells.
  • Targeting G6PD activity with specific inhibitors or manipulating its lactylation can potentially offer new treatment approaches for cervical and HPV-related cancers.

Article Abstract

High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10937312PMC
http://dx.doi.org/10.1016/j.redox.2024.103108DOI Listing

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