Senolytic Therapy: A Potential Approach for the Elimination of Oncogene-Induced Senescent HPV-Positive Cells

Abstract

Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence. Oncogenic processes that induce senescence include overexpression/hyperactivation of H-Ras, B-Raf, and cyclin E as well as inactivation of PTEN. Oncogenic viruses, such as Human Papilloma Virus (HPV), have also been shown to induce senescence. High-risk strains of HPV drive the immortalization, and hence transformation, of cervical epithelial cells via several mechanisms, but primarily via deregulation of the cell cycle, and possibly, by facilitating escape from senescence. Despite the wide and successful utilization of HPV vaccines in reducing the incidence of cervical cancer, this measure is not effective in preventing cancer development in individuals already positive for HPV. Accordingly, in this commentary, we focus on the potential contribution of oncogene and HPV-induced senescence (OIS) in cervical cancer. We further consider the potential utility of senolytic agents for the elimination of HPV-harboring senescent cells as a strategy for reducing HPV-driven transformation and the risk of cervical cancer development.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer

“…SAHF consist of a condensed chromosome enriched with histone modifications, including H3K9me3 as well as H2AX phosphorylation ( 184 ), and proteins associated with epigenetically silenced genes such as members of the E2F family ( 185 ). Further, SAHF suppress the expression of proliferative genes, including cyclin A, mediating cellular growth arrest, the common feature of senescence ( 186 ). The SASP is also regulated via various epigenetic regulators including high-mobility-group protein B2 (HMGB2) ( 187 , 188 ), mixed-lineage leukemia 1 (MLL1) ( 189 ), disruptor of telomeric silencing 1-like (DOT1L) ( 190 ), NAD-dependent deacetylase sirtuin-1 (SIRT-1) ( 191 ) and BRD4 ( 192 ).…”

Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors

“…Senescence is defined as a biological state in which cells have lost the ability to divide, but remain metabolically active for a defined period of time [ 71 , 72 , 73 , 74 ]. Three types of senescence have been identified in the literature: replicative senescence, oncogene-induced senescence and premature (accelerated, therapy- or stress-induced) senescence [ 75 , 76 ].…”

“…Three types of senescence have been identified in the literature: replicative senescence, oncogene-induced senescence and premature (accelerated, therapy- or stress-induced) senescence [ 75 , 76 ]. Senescence was recently identified as a hallmark of cancer [ 77 ]; furthermore, recovery from senescence could contribute to disease recurrence and is often associated with tumor aggressiveness and therapy resistance [ 71 , 78 , 79 ]. Senolytics, senostatics and senomorphics have been investigated recently for the possible elimination or at least extended suppression of dormant tumor cell populations [ 79 , 80 , 81 , 82 ].…”

A Conversation with ChatGPT on Contentious Issues in Senescence and Cancer Research

“…However, more recently, senescence has been recognized as a transient but durable form of growth arrest, during which cells remain metabolically active but fail to respond to mitogenic drivers (Saleh et al, 2020b;Sharpless and Sherr, 2015). Three general forms of senescence have been extensively described in the literature, specifically Replicative Senescence (RS), Oncogene-induced Senescence (OIS) as well as the primary focus for this article, therapy-induced or accelerated senescence (Gewirtz, 2009;Saleh et al, 2022c). Therapy-induced Senescence (TIS) is a state of stable growth arrest that is induced in response to different anticancer treatment modalities (Fitsiou et al, 2022).…”

“…Therapy-induced Senescence (TIS) is a state of stable growth arrest that is induced in response to different anticancer treatment modalities (Fitsiou et al, 2022). In addition to the Senescence-Associated Growth Arrest (SAGA), the senescent phenotype exhibits a range of related characteristics including enlarged and flattened morphology, increased β-galactosidase (Senescence-Associated β-galactosidase; SA-β-gal) activity (Kurz et al, 2000), accumulation of reactive oxygen species (ROS) (Nelson et al, 2018;Saleh et al, 2022c), chromatin rearrangement known as Senescence-Associated Heterochromatic Foci (SAHFs) (Zhang et al, 2005), persistent DNA damage often described as DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) (Saleh et al, 2022c), as well as secretion of an abundance of inflammatory mediators implicated in altering the surrounding microenvironment, collectively known as the Senescence-Associated Secretory Phenotype (SASP) (Gorgoulis et al, 2019). The association between TIS and the development of tumor phenotypes that likely interfere with patient responsiveness has been described, suggesting a direct relation between the senescence state and tumor recovery (Finnegan et al, 2022a), therapy resistance (Jo et al, 2023), evasion of apoptosis (Yosef et al, 2016), cellular stemness (Milanovic et al, 2018), as well as metastasis (Kawaguchi et al, 2021).…”