Exploiting pivotal mechanisms behind the senescence-like cell cycle arrest in cancer

Abstract

Senescence-like cell cycle arrest is a critical state of cancer initiation and progression. Senescence is an irreversible cell cycle arrest in response to stress induced by extrinsic and intrinsic stimuli, including oxidative/genotoxic stress, oncogenic activation, irradiation, mitochondrial malfunction, or chemotherapeutic drugs. Several signaling pathways are involved in senescence-like cell cycle arrest, which is primarily induced by the activation of p53/p21-dependent apoptotic pathways and suppressing p16INK4A/retinoblastoma protein (pRB)-dependent oncogenic pathways. p21 is necessary for proper cell cycle advancement, is involved in cell death, and mediates p53-dependent cell cycle arrest caused by DNA damage. pRB's role in tumor suppression is through modulation of the G1 checkpoint in the cell cycle, as it has the ability to block S-phase entry and cell growth. The aforementioned pathways are also highly interconnected with significant crosstalk, such as cyclin-dependent kinases (CDK)/cyclin complexes, and the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex. The primary regulators of transcription are p53 and pRB, which maintain the senescent state through negative control of the cell cycle and process of tumorigenesis. Because CDK inhibitors comprise negative regulators of cell cycle progress, they are fundamental parts of each route. Prolonged overexpression of any of these four fundamental elements (p16, p53, p21, and pRB) suffices to induce senescence, demonstrating how the regulatory DREAM complex causes senescence and how its malfunction results in cell cycle progression. The present chapter aims at revealing the pivotal mechanisms behind the senescence-like cell cycle arrest in cancer.