Cellular senescence: a promising strategy for cancer therapy

Abstract

Cellular senescence, a permanent state of cell cycle arrest, is believed to have originally evolved to limit the proliferation of old or damaged cells. However, it has been recently shown that cellular senescence is a physiological and pathological program contributing to embryogenesis, immune response, and wound repair, as well as aging and age-related diseases. Unlike replicative senescence associated with telomere attrition, premature senescence rapidly occurs in response to various intrinsic and extrinsic insults. Thus, cellular senescence has also been considered suppressive mechanism of tumorigenesis. Current studies have revealed that therapy-induced senescence (TIS), a type of senescence caused by traditional cancer therapy, could play a critical role in cancer treatment. In this review, we outline the key features and the molecular pathways of cellular senescence. Better understanding of cellular senescence will provide insights into the development of powerful strategies to control cellular senescence for therapeutic benefit. Lastly, we discuss existing strategies for the induction of cancer cell senescence to improve efficacy of anticancer therapy. [BMB Reports 2019; 52(1): 35-41].

Fig. 1

Molecular pathways of cellular senescence. DDR (DNA damage response) triggered by telomere erosion or OIS (oncogene-induced senescence) is mediated by ATM/CHK2 and ATR/CHK1, which blocks cell cycle progression via phosphorylation and stabilization of p53. Activated p53 induces transcription of CDK inhibitor p21^CIP1encoded by CDKN1A, which inhibits CDK2 activity, thereby activating RB and inducing cell cycle arrest. In parallel, various stressors also induce expression of the CDKN2A locus, which consists of p14^ARF, p16^INK4a, and p15^INK4B. p14^ARF prevents p53 destabilization by degrading the MDM2 proto-oncogene. Meanwhile, p16^INK4a and p15^INK4B suppress CDK4 and CDK6, thereby eventually activating RB. PICS (PTEN loss-induced cellular senescence) also activates p53 through the mTOR pathway. Altogether, prolonged activation of the p53/p21^CIP1 and p16^INK4a/RB signaling pathways leads to hypophosphorylation of RB, which blocks the cell cycle in G1 phase, and ultimately causes cellular senescence. RS and SIPS indicate replicative senescence and stress-induced premature senescence, respectively.