SUMMARY OF RESEARCH

1. Introduction

- The study of proteins involved in DNA repair is of extreme interest in experimental oncology. Changes in normal tissue homeostasis can derive from perturbation in the balance between the ?induced damage? and the ?residual damage? after genotoxic stress. The sensitivity of tumour cells toward DNA lesions induced by chemo and radiotherapy, might determine the efficacy of anti-tumour treatments. In this scenario, we integrate our research on the nuclear protein poly (ADP-ribose) polimerase.
Poly (ADP-ribose) polymerase (PARP-1) is a nuclear, zinc-finger, DNA-binding protein that detects specifically DNA-strand breaks generated by different genotoxic agents (de Murcia and Menissier de Murcia, 1994). PARP-1 is associated in vivo with XRCC1, a DNA repair protein involved, together with DNA polymerase b and DNA ligase III, in the base excision repair (Masson et al., 1998) of DNA. Treatment of PARP-1 ?/- mice with either alkylating agents or g-irradiation reveals an extreme sensitivity and a high genomic instability to both agents. Following whole body g-irradiation, mutant mice died rapidly from acute radiation toxicity of the small intestine (Menissier-de Murcia, 1997). Cells derived from these mice display retarded kinetics of DNA ends rejoining following damage with an alkylating agent (Trucco et al., 1998), indicating that PARP-1 is involved in base excision repair, and more precisely in the long patch pathway, probably by recruiting DNA repair enzymes to the vicinity of a DNA lesion (Dantzer F., 2000). Genetic deletion of PARP-1 attenuates tissue injury after transient cerebral ischemia (Eliasson et al., 1997), streptozotocin-induced diabetes (Masutani et al., 1999), Burkart, 1999), and pharmacological inhibition of PARP-1 improves the adverse clinical effects in different pathologies associated with inflammation (Szabo and Dawson, 1998).

2. Current research

- Our research interest is focused in elucidating the role of PARP-1 in tumorigenesis and as a tumour marker. This project involves both basic and clinical objectives and has been funded by the Spanish Ministry of Health. First, we aim to define the interaction between PARP-1 and other components of the cell machinery that cope with genotoxic damage, such as the tumour supressor protein p53 and the pro-apoptotic transcription factor NF-kB (Oliver et al., 1999 ). The clinical part of the project includes a retrospective study in biopsies of breast cancer patients, of the level of expression of PARP-1 and p53 and the correlation with clinical parameters such as the response to chemo and radioptherapy, global survival and survival without disease.
Recently we have shown that PARP-1 deficient cells are defective in NF-kB-dependent transcription activation, but not in its nuclear translocation, in response to TNFa (Oliver et al., 1999Treating mice with lipolysaccharide resulted in the rapid activation of NF-kB in macrophages from PARP-1 +/+ but not from PARP-1-/- mice. Consequently, PARP-1 deficient mice were extremely resistant to LPS-induced endotoxic shock. The molecular basis for this resistance relies on an almost complete abrogation of NF-kB-dependent accumulation of TNF-a in the serum and a down-regulation of iNOS, leading decreased NO synthesis, which is the main source of free radicals generation during inflammation. These results demonstrate a functional association in vivo between PARP-1 and NF-kB, with consequences in the transcriptional activation of NF-kB and on a systemic inflammatory process.
Recently, in collaboration with Dr. Gilbert de Murcia in Strasbourg, France, we have developed a double mutant mice for PARP-1 and p53 . A striking phenotype showing prolongation of the lifespan after knocking out PARP-1 gene in p53 -/- mice has been found (Conde et al., 2001). Elevated free radicals and NO generation has been involved in accelerated tumour progression in p53 ?mutant mice by promotion of angiogenesis (Ambs et al., 1998 ). Our hypothesis is that in the absence of PARP-1, p53-deficient mice have some advantage derived from the abrogation of NFkB activation leading to down regulation of iNOS production and of pro-apoptotic activities under the trancriptional control of NF-kB.

FUNDING AGENCIES LAST 5 YEARS

- VALIDACION CONCEPTUAL DE LA INTERACCION ENTRE TANQUIRASA(S) Y EL FACTOR INDUCIBLE POR HIPOXIA COMO NUEVA TERAPIA FRENTE AL MIMETISMO VASCULOGENICO. PROYECTO, PN2022 - PROY I+D GENERACION CONOC. - PID, Ref: PID2022-136220OB-I00, (2023 - 2027).

- Funciones de VE-Cadherina en la angiogénesis tumoral aberrante y la metástasis del melanoma. PROYECTO, J.A.- Retos de la sociedad andaluza 2020, Ref: P20_01179, (2021 - 2023).

- NUEVOS FACTORES IMPLICADOS EN EL FENOTIPO PSEUDO-ENDOTELIAL DE LAS CELULAS METASTASICAS DURANTE LA HIPOXIA Y SU PAPEL EN LA RESISTENCIA A LA TERAPIA ANTI-ANGIOGENICA. PROYECTO, PN2018 - Proyectos I+D+i «Retos Investigación», Ref: RTI2018-098968-B-I00, (2019 - 2022).

PUBLICATIONS LAST 5 YEARS

-Ana Belén Herrera-Campos; Esteban Zamudio-Martinez; Daniel Delgado-Bellido; Mónica Fernández-Cortés; Luis M Montuenga; F Javier Oliver; Angel Garcia-Diaz, Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System, Cancers, 2022, Vol. 14: 274011-2740, ARTÍCULO DE REVISIÓN, Id:894609

-Jara Majuelos-Melguizo; José Manuel Rodríguez-Vargas; Nuria Martínez-López; Daniel Delgado-Bellido; Ángel García-Díaz; Víctor J Yuste; Marina García-Macía; Laura M López; Rajat Singh; F J Oliver, Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization, Cancers, 2022, Vol. 14: 7263-726, ARTÍCULO, Id:894608

-Martí, J.M.; Garcia-Diaz, A.; Delgado-Bellido, D.; O'Valle, F.; González-Flores, A.; Carlevaris, O.; Rodríguez-Vargas, J.M.; Amé, J.C.; Dantzer, F.; King, G.L.; Dziedzic, K.; Berra, E.; de Álava, E.; Amaral, A.T.; Hammond, E.M.; Oliver, F.J., Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions, Redox Biology, 2021, Vol. 41: 101885, ARTÍCULO, Id:848789

-Zamudio-Martinez, E.; Herrera-Campos, A.B.; Muñoz, A.; Rodríguez-Vargas, J.M.; Oliver, F.J., Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities, JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2021, Vol. 40: 1-144, ARTÍCULO DE REVISIÓN, Id:846605

-Mónica Fernández-Cortés; Eduardo Andrés-León; Francisco Javier Oliver, The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry, Cells, 2020, Vol. 12: 26909-2690, ARTÍCULO, Id:820979

-José-Manuel Rodriguez-Vargas; Kathline Martin-Hernandez; Wei Wang; Nicolas Kunath; Rajikala Suganthan; Jean-Christophe Amé; F Javier Oliver; Jing Ye; Magnar Bjørås; Françoise Dantzer., Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation, Cell Death & Disease, 2020, Vol. 11: 95411-954, ARTÍCULO, Id:819466

-Calahorra, J.; Martínez-Lara, E.; Granadino-Roldán, J.M.; Martí, J.M.; Cañuelo, A.; Blanco, S.; Oliver, F.J.; Siles, E., Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells, Scientific Reports, 2020, Vol. 10: 1-6361, ARTÍCULO, Id:806413

-Martí, J.M.; Fernández-Cortés, M.; Serrano-Sáenz, S.; Zamudio-Martinez, E.; Delgado-Bellido, D.; Garcia-Diaz, A.; Oliver, F.J., The multifactorial role of PARP-1 in tumor microenvironment, Cancers, 2020, Vol. 12: 3-739, ARTÍCULO DE REVISIÓN, Id:805927

-Delgado-Bellido, D.; Bueno-Galera, C.; López-Jiménez, L.; Garcia-Diaz, A.; Oliver, F.J., Endothelial Phosphatase VE-PTP Participates in Vasculogenic Mimicry by Preventing Autophagic Degradation of VE-Cadherin, Frontiers in Oncology, 2020, Vol. 10: 18, ARTÍCULO, Id:804845

-Farias VA; Tovar I; Del Moral R; O'Valle F; Expósito J; Oliver FJ; Ruiz de Almodóvar, JM., Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes, Frontiers in Oncology, 2020, Vol. 9: 1381-1381, ARTÍCULO DE REVISIÓN, Id:777091

-Fernández-Cortés, M.; Delgado-Bellido, D.; Javier Oliver, F., Vasculogenic mimicry: Become an endothelial cell “But not so much”, Frontiers in Oncology, 2019, Vol. 9: 803, ARTÍCULO, Id:771071

-Rodríguez-Vargas, J.M.; Oliver-Pozo, F.J.; Dantzer, F., PARP1 and Poly(ADP-ribosyl)ation Signaling during Autophagy in Response to Nutrient Deprivation, Oxidative Medicine and Cellular Longevity, 2019, Vol. 2019: , ARTÍCULO DE REVISIÓN, Id:769845

-Santiago Serrano-Saenz; Carmen Palacios; Daniel Delgado-Bellido; Laura López-Jiménez; Angel Garcia-Diaz; Yolanda Soto-Serrano; J. Ignacio Casal; Rubén A. Bartolomé; José Luis Fernández-Luna; Abelardo López-Rivas; and F. Javier Oliver., PIM kinases mediate resistance of glioblastoma cells to TRAIL by a p62/SQSTM1-dependent mechanism., Cell Death & Disease, 2019, Vol. 10: 512-51, ARTÍCULO, Id:742227

-Delgado-Bellido D; Fernández-Cortés M; Rodríguez MI; Serrano-Sáenz S; Carracedo A; Garcia-Diaz A; Oliver FJ., VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression., Cell Death and Differentiation, 2019, Vol. 26: 348-361, ARTÍCULO, Id:742225

-de Araujo Farias, V.; O'Valle, F.; Serrano-Saenz, S.; Anderson, P.; Andrés, E.; López-Peñalver, J.; Tovar, I.; Nieto, A.; Santos, A.; Martín, F.; Expósito, J.; Oliver, F.J.; de Almodóvar, J.M.R., Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci, Molecular Cancer, 2018, Vol. 17: 1-122, ARTÍCULO, Id:728182

DOCTORAL THESES LAST 5 YEARS