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Review
. 2022 Dec 8;23(24):15512.
doi: 10.3390/ijms232415512.

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

Tareq Saleh  1 , Ashraf I Khasawneh  2 , Nisreen Himsawi  2 , Jumana Abu-Raideh  2 , Vera Ejeilat  3 , Ahmed M Elshazly  4   5 , David A Gewirtz  4   6
Affiliations
Review

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

Tareq Saleh et al. Int J Mol Sci. .

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.

Keywords: HPV; cervical cancer; oncogene-induced senescence; senescence; senolytics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed Model for The Contribution of HPV-Induced Senescence to Cervical Cancer. Oncogenic variants of the Human Papilloma Virus (HPV) infect basal squamous epithelial cells of the cervix ①. Fortunately, the majority of infections resolve spontaneously and are cleared within two years ②. however, approximately 1% of infected patients can develop cervical cancer ③. The oncogenic potential of HPV is primarily attributed to the oncoproteins E6 and E7, which lead to the degradation/inactivation of the tumor suppressor genes p53 ④ and ⑤ Rb, respectively. As a defense mechanism, several HPV-infected cells undergo apoptosis and are eliminated. Alternatively, cervical epithelial cells may undergo senescence as a tumor suppressor mechanism. Primarily, cells that have become dependent on E6- or E7-mediated suppression of cell cycle control can undergo senescence as a consequence to E2-mediated inactivation of E6 or E7 ⑥. Otherwise, when a naïve, virus-free cell is infected with HPV, cells undergo senescence, which is likely to represent an Oncogene-induced Senescence (OIS) variant. Oncogene-induced senescent cells infected with HPV accumulate as a component of the cervical premalignant lesion (CIN) being generated ⑦. Only those cells that manage to escape OIS or those under constant pro-tumorigenic stimulation by the SASP, are capable of progressing into malignant phenotypes ⑧. Alternatively, we propose the use of senolytics, compounds that selectively eliminate senescent cells, to interfere with the accumulation of premalignant senescent cells in cervical lesions, as a novel pharmacological approach to interfere with the development of HPV-induced cervical cancer ⑨.
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