JNK-Induced Apoptosis, Compensatory Growth, and Cancer Stem Cells

Chen, Fei

doi:10.1158/0008-5472.can-11-1982

Cited by 182 publications

(155 citation statements)

References 104 publications

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“…p38 MAPK and JNK signaling pathways are both closely associated with the initiation of apoptotic event in a various types of cells (Cuadrado et al, 2010;Chen, 2012). Many antitumor compounds are demonstrated to induce apoptosis in cancer cells by activating p-38 MAPK and/or JNK signaling (Cuadrado et al, 2010;Chen, 2012).…”

Section: Discussionmentioning

confidence: 99%

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p38 MAPK Signaling Mediates Mitochondrial Apoptosis in Cancer Cells Induced by Oleanolic Acid

Liu¹,

Wu²,

Ma³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Oleanolic acid (OA) is a nutritional component widely distributed in various vegetables. Although it has been well recognized for decades that OA exerts certain anti-tumor activity by inducing mitochondria-dependent apoptosis, it is still unclear that what molecular signaling is responsible for this effect. In this study, we employed cancer cell lines, A549, BXPC-3, PANC-1 and U2OS to elucidate the molecular mechanisms underlying OA antitumor activity. We found that activation of MAPK pathways, including p-38 MAPK, JNK and ERK, was triggered by OA in both a dose and time-dependent fashion in all the tested cancer cells. Activation was accompanied by cleavage of caspases and PARP as well as cytochrome C release. SB203580 (p38 MAPK inhibitor), but not SP600125 (JNK inhibitor) and U0126 (ERK inhibitor), rescued the pro-apoptotic effect of OA on A549 and BXPC-3 cells. OA induced p38 MAPK activation promoted mitochondrial translocation of Bax and Bim, and inhibited Bcl-2 function by enhancing their phosphorylation. OA can induce reactive oxygen species (ROS)-dependent ASK1 activation, and this event was indispensable for p38 MAPK-dependent apoptosis in cancer cells. In vivo, p38 MAPK knockdown A549 tumors proved resistant to the growth-inhibitory effect of OA. Collectively, we elucidated that activation of ROS/ASK1/p38 MAPK pathways is responsible for the apoptosis stimulated by OA in cancer cells. Our finding can contribute to a better understanding of molecular mechanisms underlying the antitumor activity of nutritional components.

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Section: Discussionmentioning

confidence: 99%

“…Many antitumor compounds are demonstrated to induce apoptosis in cancer cells by activating p-38 MAPK and/or JNK signaling (Cuadrado et al, 2010;Chen, 2012).…”

Section: Discussionmentioning

confidence: 99%

p38 MAPK Signaling Mediates Mitochondrial Apoptosis in Cancer Cells Induced by Oleanolic Acid

Liu¹,

Wu²,

Ma³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Reflecting such versatile functions of JNK in signal transduction, a growing body of evidence now suggests that JNKs may also play a significant role in the biology of human cancers (3)(4)(5). Indeed, aberrant activation of JNK has been increasingly reported in a variety of human cancers, and the roles of JNK in the control of fundamental cellular properties of cancer cells, such as proliferation, survival and migration, have been documented (2)(3)(4)(5). Significantly, adding to such roles of JNK in cancer cells in general, we and others have recently identified a specific role of JNK in the control of cancer stem cells (CSCs) of glioblastoma (5-7), a particular subpopulation of cancer cells now presumed to have a pivotal role in cancer relapse and/or metastasis as well as in therapy resistance (8,9).…”

Section: Introductionmentioning

confidence: 99%

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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“…Activation of the JNK signaling pathway in response to several extracellular stimuli has been viewed as a critical event that leads to apoptotic or non-apoptotic cell death in several cells, including bronchial epithelial, human hepatoma, hepatocellular carcinoma and osteosarcoma cells (36)(37)(38)(39). By contrast, JNK has also been reported to promote cell transformation and proliferation in cancer stem cells (40). Recent data suggest that the role of JNK1 and JNK2 in cancer is diverse, resulting in either promotion or suppression of tumor formation or size in different types of cancer, which emphasizes the significance of understanding the dual role of JNKs and the molecular background of these distinct functions in different tumors (41).…”

Section: Discussionmentioning

confidence: 99%

JNK1/2 expression and modulation of STAT3 signaling in oral cancer

et al. 2016

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Abstract. Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that link extracellular stimuli with intracellular responses and participate in numerous cellular processes such as growth, proliferation, differentiation, inflammation and apoptosis. Persistent activation of signal transducer and activator of transcription 3 (STAT3), which is accompanied by increases in STAT3 tyrosine phosphorylation, is associated with cell proliferation, differentiation and apoptosis in oral squamous cell carcinoma (OSCC). The role and significance of the activation of MAPKs, particularly of c-Jun N-terminal kinase (JNK), on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examines the effects of JNK1/2 modulation on STAT3 signaling and cellular activities in OSCC cells. The expression levels of STAT3 [total, tyrosine phosphorylated (p-Tyr) and serine phosphorylated (p-Ser)], JNK, c-Jun and cyclin D1 were assessed in the OSCC cell lines SCC25 and SCC9. Inhibition of JNK1/2 was achieved by pharmacological agents (SP600125) and by small interfering RNA (siRNA) silencing, while JNK1/2 was induced by active MAPK kinase 7. Cell proliferation and viability rates were also evaluated. Inhibition of JNK1/2 with either SP600125 treatment or specific siRNA silencing resulted in decreased levels of p-Ser STAT3 and increased levels of p-Tyr STAT3 and cyclin D1 in both cell lines. Furthermore, JNK1/2 inhibition resulted in a dose-dependent increase in cell growth and viability in both cell lines. Opposite results were observed with JNK1/2 induction in both cell lines. The present results are supportive of a potential tumor suppressive role of JNK1/2 signaling in OSCC, which may be mediated through negative crosstalk with the oncogenic STAT3 signaling pathway. The possible therapeutic implications of JNK1/2 inhibition for patients with OSCC require to be investigated.

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JNK-Induced Apoptosis, Compensatory Growth, and Cancer Stem Cells

Cited by 182 publications

References 104 publications

p38 MAPK Signaling Mediates Mitochondrial Apoptosis in Cancer Cells Induced by Oleanolic Acid

p38 MAPK Signaling Mediates Mitochondrial Apoptosis in Cancer Cells Induced by Oleanolic Acid

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

JNK1/2 expression and modulation of STAT3 signaling in oral cancer

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