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.

Figure 1

HPVs infect host epithelial cells (keratinocytes) by interacting with different cell surface receptors such as integrin and heparan sulfate proteoglycans (HSPGs). The HPVs replicate themselves using the host cell replication apparatus to express E6/E7/E5 oncoproteins to immortalize the infected cells not only by inhibiting tumour suppressors p53 and Rb and decreasing apoptosis, but also importantly by activating the PI3K/Akt/mTOR signalling pathway. All these processes enhance cell proliferation leading to the carcinogenesis. Solid line: stimulatory influence; Dashed line: inhibitory influence; ⊗: defective process.

Figure 2

HPV pseudovirions enter the host epithelial cells (keratinocytes) by interacting with α6β4 integrin receptor [154] or growth factor receptor [80] to enhance cell proliferation through the activation of the PI3K/Akt/mTOR and PI3k signalling pathway. Without the oncogenic roles of E6/E7E5, it is impossible for HPV pseudovirions to induce formation of cancerous cells by activating the PI3K/Akt signalling pathway.