Mutant p53 proteins alter signaling pathways involved in autophagy and redox regulation in cancer cells

Mutations in the TP53 gene occur in over 50% of the human cancers and most of them are missense mutations that result in the expression of mutant forms of p53. In addition, p53 mutated proteins acquire new biological properties referred as gain-of-function (GOF) that contribute to the induction and maintenance of cancer. Autophagy is an intracellular degradative process by which damaged macromolecules and organelles are targeted to lysosomes via autophagic vesicles and it is crucial to maintain primary biological activities during cellular stresses, such as nutrient starvation. Reactive oxygen species (ROS) are highly reactive byproducts of mitochondrial oxidative phosphorylation and are implicated in a plethora of biological events addressed to sustain each aspect of human cancer being able to act as second messengers in cellular signaling. The aim of this thesis was to dissect the molecular mechanisms by which oncogenic mutant p53 proteins promote cancer cell proliferation and chemoresistance in cancer cells by altering crucial signaling pathways involved in autophagy and redox homeostasis. We unveiled that GOF mutant p53 proteins, contrarily to its wild-type p53 counterpart, inhibit the autophagic pathway and enhance mitochondrial ROS in cancer cells, leading i) antiapoptotic effects, ii) proliferation and iii) chemoresistance of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes with the concomitant stimulation of mTOR signaling. Consequently to the deregulation of AMPK signaling, the expression of its effector PGC-1\u3b1 was also affected, driving a reduction of the antioxidant UCP2 protein expression and an increase of mitochondrial superoxide that acts as a critical mediator of oncogenic proprieties of mutant p53. As a paradigm of this mechanism, we showed that atg12 gene repression was mediated by the recruitment of the p50 NF-kB/mutant p53 protein complex onto two regions of the atg12 promoter suggesting the involvement of the p50-p50 homodimer as a transcriptional repressor of mutant p53 target genes. We have further correlated the low expression levels of the autophagic genes (atg12, becn1, sesn1, and dram1) with reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53- and autophagy-related signature. Intriguingly, we demonstrated that mutant p53-driven mTOR stimulation, beyond its role on autophagy repression, sensitize cancer cells carrying mutant TP53 gene to the treatment with the mTOR inhibitor everolimus. The data reported in this thesis reveal novel mechanisms by which mutant p53 sustains tumor progression and lightened on the importance that play the redox cellular status and autophagy regulation in the human tumors carrying oncogenic mutant p53 proteins

Editorial: Novel cancer treatments based on autophagy modulation

[No abstract available

Sestrins as a therapeutic bridge between ROS and autophagy in cancer

The regulation of Reactive Oxygen Species (ROS) levels and the contribution therein from networks regulating cell metabolism, such as autophagy and the mTOR-dependent nutrient-sensing pathway, constitute major targets for selective therapeutic intervention against several types of tumors, due to their extensive rewiring in cancer cells as compared to healthy cells. Here, we discuss the sestrin family of proteins-homeostatic transducers of oxidative stress, and drivers of antioxidant and metabolic adaptation-as emerging targets for pharmacological intervention. These adaptive regulators lie at the intersection of those two priority nodes of interest in antitumor intervention-ROS control and the regulation of cell metabolism and autophagy-therefore, they hold the potential not only for the development of completely novel compounds, but also for leveraging on synergistic strategies with current options for tumor therapy and classification/stadiation to achieve personalized medicine

The antioxidant mitochondrial protein UCP2 promotes cancer development connecting theWarburg effect and autophagy

Mitochondrial anion transporter proteins localized into the mitochondrial inner membrane. Currently, five UCP family members have been identified in mammals.Among them, UCP2 is widely distributedthroughout the organism, suggesting different and wide functions for this mitochondrial uncoupling protein. Basically, the antioxidant role of UCP2 is due to its capability to decrease the mitochondrial potential and to dissipate the proton gradient

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an "Achilles heel" of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene

Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective

In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.Work in the laboratories of the authors is funded by grants from the Italian Ministries for Health (Ricerca Corrente) to M.T., from Education, University and Research (MIUR; 000003_17_MAP_STRIP and FISR 2020-Covid FISR2020IP_03366) to R.S; and from the Spanish Ministerio de Ciencia e Innovación (PID2021-128106NA-I00). M.C. is currently a recipient of a Ramón y Cajal tenure track contract from the Spanish Ministry of Science and Innovation (RYC2021-031003-I) and was funded by “Maria Zambrano” contract from Spanish Ministry of Universities and Complutense University of Madrid. M.S-A is recipient of a Ramón y Cajal tenure track contract from the Spanish Ministry of Science and Innovation (RYC2020-029690-I)

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies

Sirtuins and Hypoxia in EMT Control

Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIFindependent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach

A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma.

Melanoma, a malignant form of skin cancer, has been swiftly increasing in recent years. Although there have been significant advancements in clinical treatment underlying a well-understanding of melanoma-susceptible genes and the molecular basis of melanoma pathogenesis, the permanency of response to therapy is frequently constrained by the emergence of acquired resistance and systemic toxicity. Conventional therapies, including surgical resection, chemotherapy, radiotherapy, and immunotherapy, have already been used to treat melanoma and are dependent on the cancer stage. Nevertheless, ineffective side effects and the heterogeneity of tumors pose major obstacles to the therapeutic treatment of malignant melanoma through such strategies. In light of this, advanced therapies including nucleic acid therapies (ncRNA, aptamers), suicide gene therapies, and gene therapy using tumor suppressor genes, have lately gained immense attention in the field of cancer treatment. Furthermore, nanomedicine and targeted therapy based on gene editing tools have been applied to the treatment of melanoma as potential cancer treatment approaches nowadays. Indeed, nanovectors enable delivery of the therapeutic agents into the tumor sites by passive or active targeting, improving therapeutic efficiency and minimizing adverse effects. Accordingly, in this review, we summarized the recent findings related to novel targeted therapy methods as well as nanotechnology-based gene systems in melanoma. We also discussed current issues along with potential directions for future research, paving the way for the next-generation of melanoma treatments.Sección Deptal. de Bioquímica y Biología Molecular (Biológicas)Fac. de Ciencias BiológicasTRUEEuropean UnionNextGeneration (EU/PRTR)Ministerio de Ciencia e Innovación (MICINN)/Agencia Estatal de Investigación (AEI)Ministerio de UniversidadesUniversidad Complutense de Madrid (UCM)pu

Interplay between ROS and Autophagy in Cancer and Aging: From Molecular Mechanisms to Novel Therapeutic Approaches

[no abstract available