The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis Marcel Verheij a, *, Gerald A. Ruiter a , Shuraila F. Zerp a , Wim J. van Blitterswijk b , Zvi Fuks c , Adriana Haimovitz-Friedman c , Harry Bartelink a a Department of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands b Division of Cellular Biochemistry, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands c Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Received 7 November 1997; revised version received 6 January 1998; accepted 13 January 1998 Abstract Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: SAPK/JNK; Radiation; Stress; Signal transduction; Apoptosis 1. Introduction Apoptosis, or programmed cell death, is a distinct mode of cell death and represents a major regulatory mechanism in embryonal development, growth, differentiation and nor- mal cell turnover [75]. Its significance in cancer and cancer therapy has been emphasized in several recent reviews [3,22,25,42,68]. Apoptosis is distinguished from necrosis based on specific morphologic and biochemical criteria [42] and can be induced by a variety of stimuli. These include extracellular stress (ionizing and ultraviolet (UV) radiation, heat shock, oxidative and osmotic stress and loss of cell adhesion), chemotherapeutic agents, receptor- mediated processes (tumor necrosis factor a (TNFa), CD95 and hormone/growth factor addition c.q. withdrawal) and cytotoxic lymphocytes. Although it is generally accepted that all mammalian cells constitutively express the bio- chemical apparatus to execute apoptosis, it is not clear which intracellular signal transduction pathway(s) are involved, nor to which extent different stimuli of apoptosis employ these pathway(s). Recent studies have provided important insights into the molecular mechanisms that control the execution phase of apoptosis. The final common pathway in the apoptotic machinery involves activation of a cascade of cysteine pro- teases related to interleukin-1-b-converting enzyme (ICE), also known as caspases, resulting in the cleavage of critical cellular substrates, including poly(ADP-ribose)polymerase and lamins [15,58,80]. Although activation of these cas- pases has been shown to be essential in apoptosis following triggering of death receptors, such as CD95 (Fas/APO-1) and the TNF receptor [23,58], their role in regulating the apoptotic response induced by other stimuli, including ionizing radiation, has been less well defined. The observa- Radiotherapy and Oncology 47 (1998) 225–232 0167-8140/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0167-8140(98)00007-3 * Corresponding author.