Exploring the metabolic alterations in cervical cancer induced by HPV oncoproteins: From mechanisms to therapeutic targets
Mrudula Gore, Shama Prasada Kabekkodu, Sanjiban Chakrabarty
Abstract
The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer. Cervical cancer progression is accelerated by HPV integration into host genome. Oncoproteins of HPV targets and regulates major metabolic pathways including glycolysis, lactate metabolism, fatty acid metabolism and hypoxia pathway. Altered metabolism leads to a tumor microenvironment which facilitates tumor growth and progression. Metabolic reprogramming in addition to promoting tumor growth provides novel therapeutic targets in the form of metabolic enzymes such as HK, FASN and LDHA. Green – Targets of HPV oncoproteins, Red – Inhibitors, Consecutive arrow –multiple processes in tandem. https://BioRender.com/h81e938 • Despite the availability of vaccines, cervical cancer continues to rank fourth among cancers that affect women worldwide, with approximately 660,000 new cases and approximately 350,000 deaths in 2022 with the major cause being high-risk HPVs (Human Papillomaviruses). • Through the Metabolic pathway reprogramming, cancer cells can multiply rapidly, endure hypoxia and nutrient depletion, and elude the immune system. • Reprogramming of glucose, fatty acid and amino acid metabolism in cervical cancer is linked to effects of HPV oncoproteins. • Opportunities arise from the metabolic reprogramming caused by HPV to understand the intricate mechanism involved in the progression of cervical cancer and to identify novel drug targets.