Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling

Bossler, Felicitas; Kuhn, Bianca J.; Guenther, Thomas; Kraemer, Stephen; Khalkar, Prajakta; Adrian, Svenja; Lohrey, Claudia; Holzer, Angela; Shimobayashi, Mitsugu; Mayer, Arnulf; Rösl, Frank; Grundhoff, Adam; Krijgsveld, Jeroen; Hoppe‐Seyler, Karin; Hoppe‐Seyler, Felix

doi:10.1128/mbio.02323-18

Cited by 34 publications

(65 citation statements)

References 78 publications

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“…All gynecological cancers have been reported to show an overexpression of HIF in a hypoxic environment, but data suggest that HIF enables specific isoforms of the PKC family to accumulate. As the cascade continues, this leads to an mTORC2-mediated effect currently reported only in cervical cancer [94,95]. Therefore, a further inquiry to be opened by this review is the role played by hypoxia downstream in the mTORC2 cascade.…”

Section: Resultsmentioning

confidence: 98%

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Sobočan

Bračič

Knez

et al. 2020

Cancers

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Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.

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Section: Resultsmentioning

confidence: 98%

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Sobočan

Bračič

Knez

et al. 2020

Cancers

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“…Nonetheless, a recent study showed that HPV-16 E7 can attenuate pAKT signalling [35]. In addition, hypoxic AKT activation is observed under conditions of E6/E7 repression [36], which indicates that the hypoxic AKT activation is regulated by Fig. 3 Over expression of GCN5 rescues DNA replication reduction induced by WDHD1 depletion.…”

Section: Discussionmentioning

confidence: 96%

WDHD1 facilitates G1 checkpoint abrogation in HPV E7 expressing cells by modulating GCN5

Yang

Pei

et al. 2020

BMC Cancer

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Background: Genomic instability is a hallmark of cancer. The G1 checkpoint allows cells to repair damaged DNA that may lead to genomic instability. The high-risk human papillomavirus (HPV) E7 gene can abrogate the G1 checkpoint, yet the mechanism is still not fully understood. Our recent study showed that WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein 1) plays a role in regulating G1 checkpoint of E7 expressing cells. In this study, we explored the mechanism by which WDHD1 regulates G1 checkpoint in HPV E7 expressing cells. Methods: NIKS and RPE1 derived cell lines were used. Real-time PCR, Rescue experiment, FACS and BrdU labeling experiments were performed to examine role of GCN5 in G1 checkpoint abrogation in HPV-16 E7 expressing cells. Results: In this study, we observed that WDHD1 facilitates G1 checkpoint abrogation by modulating GCN5 in HPV E7 expressing cells. Notably, depletion of WDHD1 caused G1 arrest while overexpression of GCN5 rescued the inhibitory effects of WDHD1 knockdown on G1/S progression. Furthermore, siWDHD1 significantly decreased cell cycle proliferation and DNA synthesis that was correlated with Akt phosphorylation (p-Akt), which was reversed by GCN5 overexpression in HPV E7 expressing cells. Conclusions: In summary, our data identified a WDHD1/GCN5/Akt pathway leading to the abrogation of G1 checkpoint in the presence of damaged DNA, which may cause genomic instability and eventually HPV induced tumorigenesis.

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“…Hypoxia-induced effect of the PI3K/m-TOR/AKT pathway is countered by increased activity of HIF1α which is also hypoxia dependent [65]. HIF1α through regulated in development and DNA damage response 1 (REDD1) inhibits mTORC1 signalling and stops senescence in case E6/E7 is repressed [65]. This proves that mTORC2 is still active in hypoxic environment, whereas mTORC1 shows susceptibility to oxygen shortage [66].…”

Section: Pi3k/akt/mtor Pathway Disruption By E6/e7mentioning

confidence: 92%

“…However, this was observed only for normoxic HPVpositive cells [64]. Hypoxia-induced effect of the PI3K/m-TOR/AKT pathway is countered by increased activity of HIF1α which is also hypoxia dependent [65]. HIF1α through regulated in development and DNA damage response 1 (REDD1) inhibits mTORC1 signalling and stops senescence in case E6/E7 is repressed [65].…”

Section: Pi3k/akt/mtor Pathway Disruption By E6/e7mentioning

confidence: 99%

“…Inhibition of REDD1 may reactivate mTORC1 activity and induce cell entry into senescence [67]. Even though mTORC1 activator AKT is induced in hypoxic cells, it remains downregulated, which means that REDD1 inhibiting effect is more powerful than AKT-related activation of mTORC1 [65]. It is proposed that therapy targeting the PI3K/AKT/mTOR pathway will give better perspectives in treatment of HPV-related cancer [68].…”

Section: Pi3k/akt/mtor Pathway Disruption By E6/e7mentioning

confidence: 99%

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Perspectives in HPV Secondary Screening and Personalized Therapy Basing on Our Understanding of HPV-Related Carcinogenesis Pathways

Celewicz

Michalczyk

et al. 2020

Mediators of Inflammation

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As cervical cancer is one of the most common malignancies in women worldwide even with present screening methods, the incidence in most developed countries is not decreasing for the last 15-20 years. A shift has been observed in the age of diagnosis in favour of younger women, and treatment of already developed cervical cancer is a challenge for surgeons. It is imperative to find new diagnostic methods for accurately pointing out patients at high risk of developing malignant disease and developing personalized treatment. Since cervical cancer is almost exclusively associated with HPV infection, understanding changes happening in an infected cell may prove invaluable for search of such methods, but it may also prove helpful in the diagnosis and treatment of other anogenital and nasopharyngeal region cancers. This review follows HPV-related changes in infected cell biology to point what potential markers and targets for therapy are in option when dealing with HPV-related diseases.

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Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling

Cited by 34 publications

References 78 publications

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

WDHD1 facilitates G1 checkpoint abrogation in HPV E7 expressing cells by modulating GCN5

Perspectives in HPV Secondary Screening and Personalized Therapy Basing on Our Understanding of HPV-Related Carcinogenesis Pathways

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