Novel ARF/p53-independent senescence pathways in cancer repression

Abstract

Cellular senescence, which can be induced by various stimuli, is a stress response that manifests as irreversible cell cycle arrest. Recent studies have revealed that cellular senescence can serve as a critical barrier for cancer development. Induction of cellular senescence by oncogenic insults, such as Ras overexpression or by inactivation of PTEN tumor suppressor, triggers an ARF/p53-dependent tumor-suppressive effect which can significantly restrict cancer progression. Given the important role of the ARF/p53 pathway in cellular senescence and tumor suppression, drugs that stabilize p53 expression have been developed and tested in clinical trials. However, a major hurdle for p53 targeting in cancer treatment arises from the frequent deficiency or mutation of ARF or p53 in human cancers, which, in turn, profoundly compromises their tumor-suppressive ability. Recent discoveries of novel regulators involved in ARF/p53-independent cellular senescence not only reveal novel paradigms for cellular senescence but also provide alternative approaches for cancer therapy.

Fig. 1

Cellular senescence induced by various stimuli. Telo-mere shortening, damaged DNA accumulation, oncogene/tumor suppressor dysregulation, or other stress signals (e.g., cell culture shock, interferon-β, transforming growth factor-β, or oxidative stress) will trigger cells to acquire a senescent phenotype that includes cell growth arrest, enlarged and flattened morphology, and sustained metabolic activity

Fig. 2

Novel regulators involved in p53-independent senescence pathways. Skp2 inactivation, concomitant with inactivation of PTEN, ARF, or VHL, activates downstream effectors, including p27, p21, ATF4, and p400, to mediate senescence responses. Skp2 down-regulation alone induced by HTLV Tax1 protein is also linked to cellular senescence. Inactivation of cell cycle regulators other than Skp2 (for instance, CDK2) is also engaged in senescence partially through activating p21 and p16. TAp63, which belongs to the p53 family, induces expression of p21 or pRb and subsequently contributes to the p53-independent senescent phenotype. Beyond these regulators, the senescence response is triggered by noncoding RNA. For instance, p53-independent miR-34a upregulation is involved in Braf-induced senescence by repressing Myc expression. Solid lines indicate known pathways. Dashed lines indicate undefined pathways

Fig. 3

Crosstalk between ARF, PTEN, and the Skp2-SCF complex in ARF/p53-dependent and ARF/p53-independent pathways. In response to stress signals, ARF activation and PTEN loss could trigger cellular senescence through pathways both dependent on and independent of ARF/p53. Stress stimuli induce ARF to sequester MDM2, which then activates p53 and, downstream, p21, resulting in a p53-dependent cellular senescence response. Additionally, in the absence of PTEN, stress signals will trigger p53-dependent cellular senescence through the activation of ARF or mTOR. In the context of PTEN or ARF inactivation, Skp2 deficiency will increase expression of p21, p27, and ATF4, which eventually leads to an ARF/p53-independent senescence response. Black lines indicate known pathways. Blue lines demonstrate newly characterized ARF/p53-independent pathways