Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Lee, Jang‐Jaer; Lee, J H; Ko, Young‐Gyu; Hong, Seok Il

doi:10.1038/onc.2009.355

Cited by 63 publications

(74 citation statements)

References 65 publications

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“…1B and D), suggesting that the JNK activity is required for the proliferation of A549 cells irrespective of the culture condition, at least in vitro. These results were essentially consistent with those of previous studies that demonstrated the essential role of JNK in the in vitro growth of NSCLC cells using NSCLC cell lines other than A549 (16)(17)(18).…”

Section: Rapid and Potent Inhibition Of A549 Cell Proliferation By Jnsupporting

confidence: 82%

“…Similarly to glioblastomas (12)(13)(14)(15), aberrant activation of JNK has been observed frequently in NSCLC tumors (16,17), and a number of studies do provide evidence Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells supporting the idea that JNK has a positive role in promoting the growth of NSCLC tumors (16)(17)(18). Nevertheless, evidence…”

Section: Introductionmentioning

confidence: 88%

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Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

et al. 2013

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Abstract. Deregulation of c-Jun NH 2 -terminal kinase (JNK) signaling is now increasingly reported in a variety of human malignancies. Non-small cell lung cancer (NSCLC) is among such human malignancies with aberrant JNK activation; yet the exact role(s) of JNK deregulation in NSCLC biology, in particular in vivo, remains unclear. Here, we demonstrated a specific role of JNK in the control of the tumor-initiating capacity of A549 cells derived from human lung adenocarcinoma, a major subtype of NSCLC. Despite its potent inhibitory activity on A549 cell growth in vitro, SP600125, a reversible JNK inhibitor, failed to inhibit the growth of pre-established A549 xenografts in vivo when systemically administered. Nevertheless, the same SP600125 treatment caused a marked reduction in the tumor-initiating population within the A549 tumors, suggesting that JNK may be specifically required in vivo for the maintenance of the tumor-initiating population of tumor cells rather than for proliferation and survival of the entire cell population. Furthermore, A549 cells either pretreated with SP600125 or transiently transfected with siRNAs against the JNK genes in vitro showed substantially reduced ability to initiate tumor formation upon implantation into nude mice, implying that the cell intrinsic JNK activity of A549 cells is essential for the maintenance of their tumor-initiating capacity. To our knowledge, this is the first demonstration that JNK is involved in the control of the tumor-initiating capacity of NSCLC cells. Our findings also give rise to an intriguing possibility that therapies targeting JNK could contribute to prevention of relapse and/or metastasis of NSCLC through elimination of tumor-initiating cells.

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Section: Rapid and Potent Inhibition Of A549 Cell Proliferation By Jnsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 88%

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

et al. 2013

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“…Moreover, because Sab is also a substrate of JNK (5, 6), one can speculate that JNK mitochondrial translocation is dependent upon the ability of JNK to phosphorylate Sab. JNK can then use established Bcl-2 proteins and BH3 proteins as substrates (2)(3)(4) or it can initiate new signaling cascades that result in the inhibition of respiratory Complex I. After 60 min activated JNK leaves the mitochondrial membrane (Step 3) after altering mitochondrial physiology (T), and cell death or survival functions (Step 4) are initiated.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

Chambers

LoGrasso

2011

Journal of Biological Chemistry

168

159

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The JNK signaling cascade is critical for cellular responses to a variety of environmental and cellular stimuli. Although gene expression aspects of JNK signal transduction are well studied, there are minimal data on the physiological impact of JNK signaling. To bridge this gap, we investigated how JNK impacted physiology in HeLa cells. We observed that inhibition of JNK activity and JNK silencing with siRNA reduced the level of reactive oxygen species (ROS) generated during anisomycin-induced stress in HeLa cells. Silencing p38 had no significant impact on ROS generation under anisomycin stress. Moreover, JNK signaling mediated amplification of ROS production during stress. Mitochondrial superoxide production was shown to be the source of JNK-induced ROS amplification, as an NADPH oxidase inhibitor demonstrated little impact on JNK-mediated ROS generation. Using mitochondrial isolation from JNK null fibroblasts and targeting the mitochondrial scaffold of JNK, Sab, we demonstrated that mitochondrial JNK signaling was responsible for mitochondrial superoxide amplification. These results suggest that cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and amplify up to 80% of the ROS generated largely by Complex I. This work demonstrates that a sequence of events exist for JNK mitochondrial signaling whereby ROS activates JNK, thereby affecting mitochondrial physiology, which can have effects on cell survival and death.

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“…We also previously reported that IR induces premature senescence in breast, colon, and lung carcinoma, and in tumor tissue of xenografted mice. 20,39 Therefore, understanding premature senescence mechanisms could provide helpful information for improving the efficacy of RT.…”

Section: Discussionmentioning

confidence: 99%

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

et al. 2010

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Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTENproficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.

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Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Cited by 63 publications

References 65 publications

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

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