Expression of HIF-1α and Genes Involved in Glucose Metabolism Is Increased in Cervical Cancer and HPV-16-Positive Cell Lines

Priego-Hernández, Víctor D.; Arizmendi-Izazaga, Adán; Soto-Flores, Diana G.; Santiago-Ramón, Norma; Feria-Valadez, Milagros D.; Navarro-Tito, Napoleón; Jiménez‐Wences, Hilda; Martínez‐Carrillo, Dinorah Nashely; Salmerón-Bárcenas, Eric Genaro; Leyva‐Vázquez, Marco Antonio; Illades‐Aguiar, Berenice; Alarcón‐Romero, Luz del Carmen; Ortíz-Ortíz, Julio

doi:10.3390/pathogens12010033

Cited by 15 publications

(10 citation statements)

References 61 publications

(84 reference statements)

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“…S7). Also, previous work showed that in normal cervical cells, LDH-A expression levels were significantly lower than in cervical cancer cells [13, 49]. However, in normal cells (NKE and HaCaT), we find that the dose of DCF chosen for this study (175 µM, IC 50 in HeLa cells) causes only 10% cell death compared to cancer cells (Fig.…”

Section: Discussionmentioning

confidence: 49%

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Malla,

Gupta,

Sur

2023

Preprint

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Cancer cells exhibit a unique metabolic preference for choosing the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase-A (LDH-A) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a non-steroidal anti-inflammatory drug, has been shown to exhibit anti-cancer effects by interfering with the glucose metabolism pathway. However, the specific targets remain unknown. Usingin-silico, biochemical, and biophysical studies, we show that DCF binds to LDH-A adjacent to the substrate binding site and dose-dependently inhibits its activity in an allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF fails to induce cytotoxicity in LDH-A knocked-down HeLa cells, confirming that DCF renders its anti-mitotic effects via LDH-A inhibition. DCF-induced LDH-A inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism by which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates AMPK, a sensor kinase, which further downregulates p-S6K, leading to apoptosis-mediated cell death. We find that in LDH-A knocked-down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, implying the involvement of DCF-induced LDH-A inhibition in the activation of the AMPK/S6K signaling pathway.

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Section: Discussionmentioning

confidence: 49%

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Malla,

Gupta,

Sur

2023

Preprint

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“…These results were compatible with the results of the researcher, as they indicated the presence of the close association of HIF-1α with TLR4 in cervical cancer caused by HPV infection, and detected changes in the RNA content of HIF-1α in each group to explore their correlation. The RNA content of HIF-1α was similar to TLR4, and a suggestion from these results was that the expression HIF-1α was positively associated with the expression of TLR4 in the cervix (24).…”

Section: Discussionmentioning

confidence: 61%

Role Toll-like receptor 4 gene underlying Hypoxia-inducible transcription factor 1α gene expression in cervical cancer of women

Nama¹,

Kraidi²

2023

Preprint

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Molecular methods are being used in cervical cancer screening to identify high-risk human papillomavirus. Annually, 490,000 new infections are diagnosed with papillomavirus, and about 298,000 death cases due to cervical cancer worldwide. Pap and biopsy samples from 65 samples from cervixes were collected from women with histological changes from Alsider Teaching Hospital, Maysan Hospital for Children, South of Iraq. The viruses were detected by RT-PCR in 69.2 % of the all cases. Extracted RNA samples were used to analyze the gene expression of Toll-like receptor 4 and hypoxia-inducible transcription factor 1α from biopsy samples. It was found that the number of positive samples for viruse genotype 16 was in 30 samples, which represents 66.6 %, while the genotype 18 was detected in 17 samples, which represents 37.7%, while 9 samples gave positive results for genotype 31 and represented about 20 %, relying on E6 or E7 specific primers in cDNA template by real-time PCR ,and the values of Toll-like receptor 4 in negative samples were normalized to the housekeeping gene (β actin) to 1 and its values in positive samples were compared to that 1 which was more roughly in 1-fold, and the hypoxia-inducible transcription factor 1α gene expression in positive samples was more in roughly 48-fold compared to its value in the housekeeping gene (β actin) to 1 (negative control). The study concluded that toll-like receptor 4 and hypoxia-inducible transcription factor 1α are overexpressed in cervical cancer, and both synergistically promote the development of cervical cancer.

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“…An additional effect of the presence and accumulation of HIF-1a in tumors is presumed to be the contribution to tumor chemoresistance by obstructing drug transport and uptake, whereas its overexpression is linked to worse prognosis for patients with cervical cancer [ 39 , 42 ]. On the other hand, a molecule that has given signs of decreasing cancer cell resistance to chemotherapeutics in addition to inhibiting several of the hallmarks of cancer, like proliferation, tumor invasion and metastasis, is microRNA-143 [ 43 , 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway

Konstantopoulos,

Leventakou,

Saltiel

et al. 2024

Viruses

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Human Papillomaviruses have been associated with the occurrence of cervical cancer, the fourth most common cancer that affects women globally, while 70% of cases are caused by infection with the high-risk types HPV16 and HPV18. The integration of these viruses’ oncogenes E6 and E7 into the host’s genome affects a multitude of cellular functions and alters the expression of molecules. The aim of this study was to investigate how these oncogenes contribute to the expression of immune system control molecules, using cell lines with integrated HPV16 genome, before and after knocking out E6 viral gene using the CRISPR/Cas9 system, delivered with a lentiviral vector. The molecules studied are the T-cell inactivating protein PD-L1, its transcription factor HIF-1a and the latter’s negative regulator, miR-143. According to our results, in the E6 knock out (E6KO) cell lines an increased expression of miR-143 was recorded, while a decrease in the expression of HIF-1a and PD-L1 was exhibited. These findings indicate that E6 protein probably plays a significant role in enabling cervical cancer cells to evade the immune system, while we propose a molecular pathway in cervical cancer, where PD-L1′s expression is regulated by E6 protein through a miR-143/HIF-1a axis.

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Expression of HIF-1α and Genes Involved in Glucose Metabolism Is Increased in Cervical Cancer and HPV-16-Positive Cell Lines

Cited by 15 publications

References 61 publications

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Role Toll-like receptor 4 gene underlying Hypoxia-inducible transcription factor 1α gene expression in cervical cancer of women

HPV16 E6 Oncogene Contributes to Cancer Immune Evasion by Regulating PD-L1 Expression through a miR-143/HIF-1a Pathway

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