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HPV18 oncoproteins driven expression of PKM2 reprograms HeLa cell metabolism to maintain aerobic glycolysis and viability

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Abstract

The molecular basis of human papillomavirus (HPV)-mediated cellular immortalization and malignant transformation has illustrated an indispensable role of viral E6/E7-oncoproteins. However, the impact of viral-oncoproteins on the metabolic phenotype of cancer cells remains ambiguous. We showed silencing of HPV18-encoded E6/E7-oncoprotein significantly reduced glucose consumption, lactate production, ATP level and viability. Silencing of HPV18-encoded E6/E7 in HeLa cells significantly down-regulated expression and activity of HK1, HK2, LDHA, and LDHB. Interestingly, there was an increased pyruvate kinase activity due to switch in expression from PKM2 isoform to PKM1. The switch in favor of alternatively spliced isoform PKM1, was regulated by viral-E6/E7-oncoprotein by inhibiting the c-Myc/hnRNP-axis. Further, the near absence of the PKM1 protein despite an adequate amount of PKM1 mRNA in HeLa cells was due to its proteasomal degradation. Our results suggests HPV18-encoded E6/E7 driven preferential expression of PKM2 is essential to support aerobic glycolysis and cell proliferation.

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Acknowledgements

This work was partially supported by University Grant Commission (UGC), Government of India, the grant (F. No 17-4/2001 (NS/PE) provided to the National Centre of Applied Human Genetics (to RNKB). The work was also supported by Department of Biotechnology, Government of India under award number BT/RLF/Re-entry/23/2018 (to RKS). G.P. acknowledges UGC for providing meritorious science research Fellowship.

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Authors and Affiliations

  1. School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Gopinath Prakasam & Rameshwar N. K. Bamezai

  2. Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India

    Mohammad Askandar Iqbal

  3. Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Anusha Srivastava & Rajnish Kumar Singh

  4. Delhi School of Public Health, University of Delhi, New Delhi, 110007, India

    Rameshwar N. K. Bamezai

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Prakasam, G., Iqbal, M.A., Srivastava, A. et al. HPV18 oncoproteins driven expression of PKM2 reprograms HeLa cell metabolism to maintain aerobic glycolysis and viability. VirusDis. 33, 223–235 (2022). https://doi.org/10.1007/s13337-022-00776-w

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