Senescence program and its reprogramming in pancreatic premalignancy

Abstract

Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each other, they have similar mechanisms in many aspects. Pancreatic ductal adenocarcinoma (PDA) is highly lethal disease, which occurs and progresses through a multi-step process. Senescence is prevalent in pancreatic premalignancy, as manifested by decreased cell proliferation and increased clearance of pre-malignant cells by immune system. However, the senescent microenvironment cooperates with multiple factors and significantly contributes to tumorigenesis. Evidently, PDA progression requires to evade the effects of cellular senescence. This review will focus on dual roles that senescence plays in PDA development and progression, the signaling effectors that critically regulate senescence in PDA, the identification and reactivation of molecular targets that control senescence program for the treatment of PDA.

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling

“…This senescence bypass mechanism involves the upregulation of the basic helix-loop-helix transcription factor Twist, which, in turn, prevents the induction of p16INK4A [202]. KRAS activates the senescence program through three signals [203]: (1) PI3K activation downstream of KRAS [204], (2) Activin A activation [204], and (3) CXCL1 and CXCR2 axes [205]. These findings imply that Rheb1 may play an integral role in cellular immortalization and senescence.…”