Publications by authors named "Alfredo Cruz-Gregorio"

11 Publications

  • Page 1 of 1

Lipid metabolism and oxidative stress in HPV-related cancers.

Free Radic Biol Med 2021 Jun 12;172:226-236. Epub 2021 Jun 12.

IHuman Institute, ShanghaiTech University, China; Laboratorio F-206, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico. Electronic address:

High-risk human papillomavirus (HR-HPVs) are associated with the development of cervical, anus, vagina, vulva, penis, and oropharynx cancer. HR-HPVs target and modify the function of different cell biomolecules such as glucose, amino acids, lipids, among others. The latter induce cell proliferation, cell death evasion, and genomic instability resulting in cell transformation. Moreover, lipids are essential biomolecules in HR-HPVs infection and cell vesicular trafficking. They are also critical in producing cellular energy, the epithelial-mesenchymal transition (EMT) process, and therapy resistance of HPV-related cancers. HPV proteins induce oxidative stress (OS), which in turn promotes lipid peroxidation and cell damage, resulting in cell death such as apoptosis, autophagy, and ferroptosis. HR-HPV-related cancer cells cope with OS and lipid peroxidation, preventing cell death; however, these cells are sensitized by OS, which could be used as a target for redox therapies to induce their elimination. This review focuses on the role of lipids in HR-HPV infection and HPV-related cancer development, maintenance, resistance to therapy, and the possible treatments associated with lipids. Furthermore, we emphasize the significant role of OS in lipid peroxidation to induce cell death through apoptosis, autophagy, and ferroptosis to eliminate HPV-related cancers.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.06.009DOI Listing
June 2021

Redox signaling pathways in unilateral ureteral obstruction (UUO)-induced renal fibrosis.

Free Radic Biol Med 2021 May 30;172:65-81. Epub 2021 May 30.

Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, Mexico. Electronic address:

Unilateral ureteral obstruction (UUO) is an experimental rodent model that mimics renal fibrosis associated with obstructive nephropathy in an accelerated manner. After UUO, the activation of the renin-angiotensin system (RAS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and mitochondrial dysfunction lead to reactive oxygen species (ROS) overproduction in the kidney. ROS are secondary messengers able to induce post-translational modifications (PTMs) in redox-sensitive proteins, which activate or deactivate signaling pathways. Therefore, in UUO, it has been proposed that ROS overproduction causes changes in said pathways promoting inflammation, oxidative stress, and apoptosis that contribute to fibrosis development. Furthermore, mitochondrial metabolism impairment has been associated with UUO, contributing to renal damage in this model. Although ROS production and oxidative stress have been studied in UUO, the development of renal fibrosis associated with redox signaling pathways has not been addressed. This review focuses on the current information about the activation and deactivation of signaling pathways sensitive to a redox state and their effect on mitochondrial metabolism in the fibrosis development in the UUO model.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.034DOI Listing
May 2021

Redox-sensitive signalling pathways regulated by human papillomavirus in HPV-related cancers.

Rev Med Virol 2021 Mar 11:e2230. Epub 2021 Mar 11.

Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, México City, México.

High-risk human papillomavirus (HR-HPV) chronic infection is associated with the induction of different HPV-related cancers, such as cervical, anus, vaginal, vulva, penis and oropharynx. HPV-related cancers have been related to oxidative stress (OS), where OS has a significant role in cancer development and maintenance. Surgical resection is the treatment of choice for localised HPV-related cancers; however, these malignancies commonly progress to metastasis. In advanced stages, systemic therapies are the best option against HPV-related cancers. These therapies include cytokine therapy or a combination of tyrosine kinase inhibitors with immunotherapies. Nevertheless, these strategies are still insufficient. Cell redox-sensitive signalling pathways have been poorly studied, although they have been associated with the development and maintenance of HPV-related cancers. In this review, we analyse the known alterations of the following redox-sensitive molecules and signalling pathways by HR-HPV in HPV-related cancers: MAPKs, Akt/TSC2/mTORC1, Wnt/β-Cat, NFkB/IkB/NOX2, HIF/VHL/VEGF and mitochondrial signalling pathways as potential targets for redox therapy.
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http://dx.doi.org/10.1002/rmv.2230DOI Listing
March 2021

Regulation of autophagy by high- and low-risk human papillomaviruses.

Rev Med Virol 2021 Mar 17;31(2):e2169. Epub 2020 Sep 17.

Laboratorio 315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, México.

While high-risk human papillomavirus (HR-HPV) infection is related to the development of cervical, vulvar, anal, penile and oropharyngeal cancer, low-risk human papillomavirus (LR-HPV) infection is implicated in about 90% of genital warts, which rarely progress to cancer. The carcinogenic role of HR-HPV is due to the overexpression of HPV E5, E6 and E7 oncoproteins which target and modify cellular proteins implicated in cell proliferation, apoptosis and immortalization. LR-HPV proteins also target and modify some of these processes; however, their oncogenic potential is lower than that of HR-HPV. HR-HPVs have substantial differences with LR-HPVs such as viral integration into the cell genome, induction of p53 and retinoblastoma protein degradation, alternative splicing in HR-HPV E6-E7 open reading frames, among others. In addition, LR-HPV can activate the autophagy process in infected cells while HR-HPV infection deactivates it. However, in cancer HR-HPV might reactivate autophagy in advance stages. Autophagy is a catabolic process that maintains cell homoeostasis by lysosomal degradation and recycling of damaged macromolecules and organelles; nevertheless, depending upon cellular context autophagy may also induce cell death. Therefore, autophagy can contribute either as a promotor or as a suppressor of tumours. In this review, we focus on the role of HR-HPV and LR-HPV in autophagy during viral infection and cancer development. Additionally, we review key regulatory molecules such as microRNAs in HPV present during autophagy, and we emphasize the potential use of cancer treatments associated with autophagy in HPV-related cancers.
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http://dx.doi.org/10.1002/rmv.2169DOI Listing
March 2021

Ergosterol Peroxide Isolated from Oyster Medicinal Mushroom, Pleurotus ostreatus (Agaricomycetes), Potentially Induces Radiosensitivity in Cervical Cancer.

Int J Med Mushrooms 2020 ;22(11):1109-1119

Centro de Investigación de Micología Aplicada, Universidad Veracruzana, 91010, Xalapa, Veracruz, Mexico.

Every year, more than 500,000 new cases of cervical cancer are reported, making it the fourth leading cause of cancer globally. Although human papillomavirus (HPV) vaccines show promise as a protective measure, HPV-related cancers remain a public health problem since the vaccines, which are only specific to certain viral types, are unavailable for mass distribution. Furthermore, the effects of toxicity following ionizing radiation therapy have reoriented views toward the search for radiosensitizers that can reduce toxicity as a consequence of decreased radiation doses. Here, we isolated ergosterol peroxide (EP) from Pleurotus ostreatus and purified it to test its potential effects in vitro. We thus observed that a gradual increase in EP dose correlates with a loss of viability in HeLa and CaSki cervical cell lines. Dose/response curves were constructed using cervical cancer cell lines, as well as normal human peripheral blood mononuclear cells. The selectivity of EP in human lymphocytes and cervical cancer cell lines was tested, and no toxicity was found in normal cells. A combination of treatments revealed a radiosensitizer effect in HeLa cells, when measuring the exposure to EP followed by irradiation with 137Cs. Our findings suggest that EP may be effective as a radiosensitizer in treating cervical cancer.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2020036673DOI Listing
July 2021

Human Papillomavirus-related Cancers and Mitochondria.

Virus Res 2020 09 20;286:198016. Epub 2020 May 20.

Faculty of Chemistry, Biology Department, Laboratories F-315, National Autonomous University of Mexico, CDMX, 04510, Mexico. Electronic address:

Although it has been established that persistent infection with high risk human papillomavirus (HR-HPV) is the main cause in the development of cervical cancer, the HR-HPV infection is also related with the cause of a significant fraction of other human malignancies from the mucosal squamous epithelial such as anus, vagina, vulva, penis and oropharynx. HR-HPV infection induces cell proliferation, cell death evasion and genomic instability resulting in cell transformation, due to HPV proteins, which target and modify the function of differents cell molecules and organelles, such as mitochondria. Mitochondria are essential in the production of the cellular energy by oxidative phosphorylation (OXPHOS), in the metabolism of nucleotides, aminoacids (aa), and fatty acids, even in the regulation of cell death processes such as apoptosis or mitophagy. Thus, mitochondria have a significant role in the HPV-related cancer development. This review focuses on the role of HPV and mitochondria in HPV-related cancer development, and treatments associated to mitochondrial apoptosis.
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http://dx.doi.org/10.1016/j.virusres.2020.198016DOI Listing
September 2020

E6 Oncoproteins from High-Risk Human Papillomavirus Induce Mitochondrial Metabolism in a Head and Neck Squamous Cell Carcinoma Model.

Biomolecules 2019 08 8;9(8). Epub 2019 Aug 8.

Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, México/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México. San Fernando No. 22, Col. Sección XVI, Tlalpan, Ciudad de México 14080, Mexico.

Head and neck squamous cell carcinoma (HNSCC) cells that are positive for human papillomavirus (HPV+) favor mitochondrial metabolism rather than glucose metabolism. However, the involvement of mitochondrial metabolism in HNSCC HPV+ cells is still unknown. The aim of this work was to evaluate the role of E6 oncoproteins from HPV16 and HPV18 in the mitochondrial metabolism in an HNSCC model. We found that E6 from both viral types abates the phosphorylation of protein kinase B-serine 473 (pAkt), which is associated with a shift in mitochondrial metabolism. E6 oncoproteins increased the levels of protein subunits of mitochondrial complexes (I to IV), as well as the ATP synthase and the protein levels of the voltage dependent anion channel (VDAC). Although E6 proteins increased the basal and leak respiration, the ATP-linked respiration was not affected, which resulted in mitochondrial decoupling. This increase in leak respiration was associated to the induction of oxidative stress (OS) in cells expressing E6, as it was observed by the fall in the glutathione/glutathione disulfide (GSH/GSSG) rate and the increase in reactive oxygen species (ROS), carbonylated proteins, and DNA damage. Taken together, our results suggest that E6 oncoproteins from HPV16 and HPV18 are inducers of mitochondrial metabolism.
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http://dx.doi.org/10.3390/biom9080351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722992PMC
August 2019

Reprogramming of Energy Metabolism in Response to Radiotherapy in Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2019 Feb 5;11(2). Epub 2019 Feb 5.

Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, México/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, San Fernando No. 22, Col. Sección XVI, Tlalpan, Ciudad de México 14080, México.

Head and neck cancer (HNC) is the sixth cause of cancer-related death worldwide. Head and neck squamous cells carcinoma (HNSCC) is the most frequent subtype of HNC. The development of HNSCC is associated to alcohol consumption, smoking or infection by high-risk human Papillomavirus (HR-HPV). Although the incidence of cancers associated with alcohol and tobacco has diminished, HNSCC associated with HR-HPV has significantly increased in recent years. However, HPV-positive HNSCC responds well to treatment, which includes surgery followed by radiation or chemoradiation therapy. Radiation therapy (RT) is based on ionizing radiation (IR) changing cell physiology. IR can directly interact with deoxyribonucleic acid (DNA) or produce reactive oxygen and nitrogen species (RONS), provoking DNA damage. When DNA damage is not repaired, programmed cell death (apoptosis and/or autophagy) is induced. However, cancer cells can acquire resistance to IR avoiding cell death, where reprogramming of energy metabolism has a critical role and is intimately connected with hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy. This review is focused on the reprogramming of energy metabolism in response to RT in HPV-positive and HPV-negative HNSCC, showing their differences in cellular metabolism management and the probable direction of treatments for each subtype of HNSCC.
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http://dx.doi.org/10.3390/cancers11020182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406552PMC
February 2019

Regulation of Cellular Metabolism by High-Risk Human Papillomaviruses.

Int J Mol Sci 2018 06 22;19(7). Epub 2018 Jun 22.

Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología (INCan)/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City 14080, Mexico.

The alteration of glucose metabolism is one of the first biochemical characteristics associated with cancer cells since most of these cells increase glucose consumption and glycolytic rates even in the presence of oxygen, which has been called “aerobic glycolysis” or the Warburg effect. Human papillomavirus (HPV) is associated with approximately 5% of all human cancers worldwide, principally to cervical cancer. E6 and E7 are the main viral oncoproteins which are required to preserve the malignant phenotype. These viral proteins regulate the cell cycle through their interaction with tumor suppressor proteins p53 and pRB, respectively. Together with the viral proteins E5 and E2, E6 and E7 can favor the Warburg effect and contribute to radio- and chemoresistance through the increase in the activity of glycolytic enzymes, as well as the inhibition of the Krebs cycle and the respiratory chain. These processes lead to a fast production of ATP obtained by Warburg, which could help satisfy the high energy demands of cancer cells during proliferation. In this way HPV proteins could promote cancer hallmarks. However, it is also possible that during an early HPV infection, the Warburg effect could help in the achievement of an efficient viral replication.
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http://dx.doi.org/10.3390/ijms19071839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073392PMC
June 2018

Human Papillomavirus Types 16 and 18 Early-expressed Proteins Differentially Modulate the Cellular Redox State and DNA Damage.

Int J Biol Sci 2018 1;14(1):21-35. Epub 2018 Jan 1.

Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, México/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México. San Fernando No. 22, Col. Sección XVI, Tlalpan, 14080 Ciudad de México, México.

Oxidative stress has been proposed as a risk factor for cervical cancer development. However, few studies have evaluated the redox state associated with human papillomavirus (HPV) infection. The aim of this work was to determine the role of the early expressed viral proteins E1, E2, E6 and E7 from HPV types 16 and 18 in the modulation of the redox state in an integral form. Therefore, generation of reactive oxygen species (ROS), concentration of reduced glutathione (GSH), levels and activity of the antioxidant enzymes catalase and superoxide dismutase (SOD) and deoxyribonucleic acid (DNA) damage, were analysed in epithelial cells ectopically expressing the viral proteins. Our research shows that E6 oncoproteins decreased GSH and catalase protein levels, as well as its enzymatic activity, which was associated with an increase in ROS production and DNA damage. In contrast, E7 oncoproteins increased GSH, as well as catalase protein levels and its activity, which correlated with a decrease in ROS without affecting DNA integrity. The co-expression of both E6 and E7 oncoproteins neutralized the effects that were independently observed for each of the viral proteins. Additionally, the combined expression of E1 and E2 proteins increased ROS levels with the subsequent increase in the marker for DNA damage phospho-histone 2AX (γH2AX). A decrease in GSH, as well as SOD2 levels and activity were also detected in the presence of E1 and E2, even though catalase activity increased. This study demonstrates that HPV early expressed proteins differentially modulate cellular redox state and DNA damage.
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http://dx.doi.org/10.7150/ijbs.21547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821046PMC
February 2019

Cellular redox, cancer and human papillomavirus.

Virus Res 2018 02 11;246:35-45. Epub 2018 Jan 11.

Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, San Fernando No. 22, Col. Sección XVI, Tlalpan, 14080 Ciudad de México, Mexico; Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico. Electronic address:

High-risk Human Papillomavirus (HR-HPV) is the causative agent of different human cancers. A persistent HR-HPV infection alters several cellular processes involved in cell proliferation, apoptosis, immune evasion, genomic instability and transformation. Cumulative evidence from past studies indicates that HR-HPV proteins are associated with oxidative stress (OS) and has been proposed as a risk factor for cancer development. Reactive oxygen and nitrogen species (RONS) regulate a plethora of processes inducing cellular proliferation, differentiation and death. Oxidative stress (OS) is generated when an imbalance in the redox state occurs due to deregulation of the oxidant and antioxidant systems, which, in turn, promotes the damage of DNA, proteins and lipids, allowing the accumulation of mutations and genome instability. OS has been associated with the establishment and development of different cancers, and it has recently been proposed as a co-factor in cervical cancer development. This review is focused on evidence regarding the association of OS with HR-HPV proteins, and the interplay of the viral proteins with different elements of the antioxidant and DNA damage response (DDR) systems, emphasizing the processes that might be required for the viral life cycle and viral DNA integration into the host genome, which is a key element in the carcinogenic process induced by HR-HPV.
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http://dx.doi.org/10.1016/j.virusres.2018.01.003DOI Listing
February 2018
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