The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways

Morales-García, Vicente; Contreras‐Paredes, Adriana; Martínez-Abundis, Eduardo; Gómez-Crisóstomo, Nancy Patricia; Lizano, Marcela; Hernandez-Landero, Fernanda; Cruz-Hernández, Erick de la

doi:10.1002/2211-5463.12987

Cited by 10 publications

(7 citation statements)

References 34 publications

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“…Cyclins D1 and E1 (encoded by CCND1 and CCNE1 , respectively) are responsible for cell cycle progression. The oncoprotein E6 of HPV can activate the transcription factor eIF4E, and its inhibition in cervical cancer cell lines leads to CCND1 downregulation 50 . Interestingly, cyclin D1 leads to the release of E2F by inducing phosphorylation of pRB, a protein that is already targeted by HPV oncoprotein E7 51 , 52 .…”

Section: Discussionmentioning

confidence: 99%

TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line

Morale

Tamura

Cintra

et al. 2022

Sci Rep

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Human Papillomavirus is responsible for a wide range of mucosal lesions and tumors. The immune system participate in tumorigenesis in different ways. For example, signaling pathways triggered by Toll-like receptors (TLR) play a role in chemotherapy resistance in several tumor types and are candidates for contributing to the development of HPV-induced tumors. Here, we studied the receptor TLR4 and the adaptor molecule SARM1 in HeLa cells, an HPV-positive cervical cancer cell line. Knocking out of these genes individually proved to be important for maintaining cell viability and proliferation. TLR4 knock out cells were more sensitive to cisplatin treatment, which was illustrated by an increased frequency of apoptotic cells. Furthermore, TLR4 and SARM1 modulated ROS production, which was induced by cell death in response to cisplatin. In conclusion, TLR4 and SARM1 are important for therapy resistance and cervical cancer cell viability and may be relevant clinical targets.

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Section: Discussionmentioning

confidence: 99%

TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line

Morale

Tamura

Cintra

et al. 2022

Sci Rep

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“…Some of these genes are related to cell cycle‐related proteins. Studies have demonstrated that HPVE6 upregulates the expression of eIF5A‐1 145 and modulates the activity of eIF4E protein through the MEK/ERK and AKT/PKB pathways 146 . HPV16 E7 increases the expression of pyruvate kinaseM2 (PKM2) and trriggers its nonglycolytic function, fostering cervical cancer cell proliferation 147 .…”

Section: Hpv and Its Pathogenesismentioning

confidence: 99%

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Ye,

Zheng,

et al. 2023

MedComm

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Human papillomavirus (HPV) is the most prevalent sexually transmitted virus globally. Persistent high‐risk HPV infection can result in cervical precancerous lesions and cervical cancer, with 70% of cervical cancer cases associated with high‐risk types HPV16 and 18. HPV infection imposes a significant financial and psychological burden. Therefore, studying methods to eradicate HPV infection and halt the progression of precancerous lesions remains crucial. This review comprehensively explores the mechanisms underlying HPV‐related cervical lesions, including the viral life cycle, immune factors, epithelial cell malignant transformation, and host and environmental contributing factors. Additionally, we provide a comprehensive overview of treatment methods for HPV‐related cervical precancerous lesions and cervical cancer. Our focus is on immunotherapy, encompassing HPV therapeutic vaccines, immune checkpoint inhibitors, and advanced adoptive T cell therapy. Furthermore, we summarize the commonly employed drugs and other nonsurgical treatments currently utilized in clinical practice for managing HPV infection and associated cervical lesions. Gene editing technology is currently undergoing clinical research and, although not yet employed officially in clinical treatment of cervical lesions, numerous preclinical studies have substantiated its efficacy. Therefore, it holds promise as a precise treatment strategy for HPV‐related cervical lesions.

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“…Saha et al reported that AKT upregulates TKT activity by promoting phosphorylation of TKT Thr382, 43 whereas several studies have shown that HPV16 E6 can activate AKT. [44][45][46] Thus, we reasoned that HPV16 E6 oncogene might upregulate TKT enzymatic activity by activating AKT.…”

Section: Hpv16 E6 Upregulates Tkt Activity Via Akt Activationmentioning

confidence: 99%

Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B

Hao,

Meng,

Sun

et al. 2023

Molecular Carcinogenesis

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Over 99% of precancerous cervical lesions are associated with human papillomavirus (HPV) infection, with HPV types 16 and 18 (especially type 16) found in over 70% of cervical cancer cases globally. E6, a critical HPV gene, triggers malignant proliferation by degrading p53; however, this mechanism alone cannot fully explain the oncogenic effects of HPV16 E6. Therefore, we aimed to investigate new targets of HPV oncogenic mechanisms. Our results revealed significant changes in nonoxidative pentose phosphate pathway (PPP) metabolites in HPV16‐positive cells. However, the role of nonoxidative PPP in HPV‐associated cell transformation and tumor development remained unexplored. In this study, we investigated the impact and mechanisms of HPV16 E6 on cervical cancer proliferation using the HPV‐negative cervical cancer cell line (C33A). HPV16 E6 was found to promote cervical cancer cell proliferation both in vitro and in vivo, activating the nonoxidative PPP. Transketolase (TKT), a key enzyme in the nonoxidative PPP, is highly expressed in cervical cancer tissues and associated with poor prognosis. HPV16 E6 promotes cervical cancer cell proliferation by upregulating TKT activity through the activation of AKT. In addition, oxythiamine (OT), a TKT inhibitor, hindered tumor growth, with enhanced effects when combined with cisplatin (DDP). In conclusion, HPV16 E6 promotes cervical cancer proliferation by upregulating TKT activity through the activation of AKT. OT demonstrates the potential to inhibit HPV16‐positive cervical cancer growth, and when combined with DDP, could further enhance the tumor‐suppressive effect of DDP.

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The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways

Cited by 10 publications

References 34 publications

TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line

TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B

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