The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses

Abstract

Infection with Human papillomaviruses (HPVs) leads to the development of a wide-range of cancers, accounting for 5% of all human cancers. A prominent example is cervical cancer, one of the leading causes of cancer death in women worldwide. It has been well established that tumor development and progression induced by HPV infection is driven by the sustained expression of two oncogenes E6 and E7. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways that may be equally important for transformation. Among these pathways, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling cascade plays a very important role in HPV-induced carcinogenesis by acting through multiple cellular and molecular events. In this review, we summarize the frequent amplification of PI3K/Akt/mTOR signals in HPV-induced cancers and discuss how HPV oncogenes E6/E7/E5 activate the PI3K/Akt/mTOR signalling pathway to modulate tumor initiation and progression and affect patient outcome. Improvement of our understanding of the mechanism by which the PI3K/Akt/mTOR signalling pathway contributes to the immortalization and carcinogenesis of HPV-transduced cells will assist in devising novel strategies for preventing and treating HPV-induced cancers.

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

“…Mutation data from many independent studies showed mutations in PIK3CA and PTEN in various proportions in cervical cancer (13%‐23% in PIK3CA, 5%‐8% in PTEN) 20. A recent review found that HPV oncogenes E6/E7/E5 enhance the PI3K/AKT/mTOR signalling pathway by directly activating PI3K and the downstream AKT and p70S6K, which consequently modulates tumour initiation and progression as well as patient outcome in cervical cancer 21. As a negative regulatory molecule of the PI3K/AKT pathway, INPP4B has been reported to have tumour suppression effects in various tumours 9, 10, 11, 12.…”

Emerging strategies for targeting PI3K in gynecologic cancer

“…Recently, Zhang and colleagues published a comprehensive review highlighting how HPV's oncogenic proteins E5, E6, E7 enhance PI3K pathway signaling via direct activation of PI3K as well as downstream AKT and rpS6K. In addition, these proteins appear to induce ligand dependent signaling indirectly through epidermal growth factor receptor (EGFR) [56,57]. The specific activities of E5, E6, and E7 have been recently reviewed by Chen and colleagues.…”

HIF-1α and mTOR – Possible Novel Strategies of Targeted Therapies in p16-positive and -negative HNSCC

“…The results, therefore, suggest indirect inhibiting mechanisms of mTOR by the inhibition of upstream regulators as PI3K which are affected by activated extracellular protein ligands like EGFR. The activation of mTOR in HPV-related tumors occurs in more than 60%, outlining the significant role of mTOR in the appearance of p16-associated tumors (52). In our previous work we already showed a distinct decrease of mTOR expression in both p16-negative and p16-positive squamous cancer cells by direct mTOR inhibition (53).…”

“…In our previous work we already showed a distinct decrease of mTOR expression in both p16-negative and p16-positive squamous cancer cells by direct mTOR inhibition (53). The activity of mTOR can be regulated through AKT signalling and through direct enhanced phosphorylation of mTOR through p16-associated oncoprotein E6 (52). Indirect inhibition of mTOR through PDGFR inhibition or EGFR inhibition significantly reduced mTOR expression in p16-associated tumor cells.…”