ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation

Abstract

AMPK is a serine/threonine protein kinase family and we recently identified a novel member, ARK5. The activation of ARK5 is triggered by Akt, and ARK5 induces tumor cell survival during nutrient starvation. In the current study, we investigated the mechanisms of induction of cell survival by ARK5. Human hepatoma HepG2 cells undergo necrotic cell death within 24 h after the start of glucose starvation, and the cell death signaling has been found to be mediated by death-receptor-independent activation of caspase 8. When HepG2 cells were transfected with ARK5 expression vector and subjected to several cell death stimuli, ARK5 was found to suppress cell death by glucose starvation, TRAIL, and TNF-a, but not by ultraviolet irradiation, camptothecin, or doxorubicin. Western blotting analysis revealed that both TRAIL and glucose starvation induced Bid cleavage and FLIP degradation following caspase 8 activation in a timedependent manner, and ARK5 overexpression clearly delayed Bid cleavage, FLIP degradation, and caspase 8 activation. On the basis of the results of this study, we report that cell survival induced by ARK5 is, at least in part, due to inhibition of caspase 8 activation.

Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

“…When the cells were stained with propidium iodide and Hoechst 33342 after having been treated with kigamicin D under nutrient starvation, most of the cells were stained with propidium iodide without nuclear fragmentation or chromatin condensation, similar to cells treated with DMSO (Fig. 3A), which was used as the control of necrosis, 16) indicating the occurrence of necrotic cell death. 15) These cells showed positive staining with propidium iodide without annexin V staining on FACS analysis, at least in their early stage of death (Fig.…”

“…We also observed that activation of Akt/ARK5 can rescue cancer cells from necrosis induced by nutrient starvation, suggesting that Akt plays a critical role in the necrosis of cancer cells. 16) Therefore, the inhibition of Akt phosphorylation should, at least in part, be responsible for the preferential cytotoxicity of kigamicin D. On the other hand, an antisense RNA expression vector for Akt significantly diminished the tolerance of PANC-1 cells to nutrient starvation. However, wortmannin and LY294002 do not kill cancer cells under the same conditions, although Akt phosphorylation (Ser-473) was completely inhibited by these two compounds.…”

“…34) Another possibility is that an anti-apoptotic pathway is activated in PANC-1 cells when they are subjected to nutrient starvation. 16,35) The mechanisms of the loss of anticancer activity may be different among different drugs. The precise mechanism still needs to be elucidated, but it is reasonable to assume that kigamicin D is a different type of anticancer drug.…”

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

“…The study of the biological function of NUAK1 has suggested that it is involved in tumor invasion, metastasis and apoptosis resistance (Suzuki et al, 2003a(Suzuki et al, , b, 2004a(Suzuki et al, , b, 2005Kusakai et al, 2004a, b). However, NUAK1 was also reported to be phosphorylated and activated by major tumor suppressor LKB1 (Lizcano et al, 2004).…”

“…During glucose deprivation or response to adenosine monophosphate, NUAK1 has been reported to support the survival of cells in an Aktdependent manner (Suzuki et al, 2003b). Evidence has shown that NUAK1 suppresses cell death induced by nutrient starvation and activation of death receptors through inhibition of caspase 8, as well as negative regulation of procaspase 6 (Suzuki et al, 2003a. Together with reports that NUAK1 is strongly associated with tumor invasion and metastasis, it has been proposed that NUAK1 is a tumor survival and tumor progression factor (Kusakai et al, 2004a, b;Suzuki et al, 2004b).…”