Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells

Kim, Yong Keun; Kim, Hyun Ju; Kwon, Chae Hwa; Kim, Jae Ho; Woo, Jae Suk; Jung, Jin Sup; Kim, Jong Min

doi:10.1002/jat.1081

Cited by 154 publications

(121 citation statements)

References 52 publications

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“…16,43 Although GFR was not measured, biochemical ERK inhibition promoted the retention of focal adhesions and preserved the actin cytoskeletal network in a single study of renal ischemia. 44 In contrast to ischemia/reperfusion models, ERK inhibition (versus activation) protects against cis-platinum-induced AKI, partly by its effect on apoptosis inhibition 45 and partly by modulating renal epithelial cell cilia. 46 However, few studies (including the present report) have used molecular techniques to selectively manipulate individual ERKs.…”

Section: Discussionmentioning

confidence: 99%

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Gall

Wang

Bonegio

et al. 2015

Journal of the American Society of Nephrology

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Proximal tubule (PT) cells are critical targets of acute ischemic injury. Elimination of the mitochondrial fusion protein mitofusin 2 (Mfn2) sensitizes PT cells to apoptosis in vitro. However, the role of PT Mfn2 in ischemic AKI in vivo is unknown. To test its role, we evaluated the effects of conditional KO of PT Mfn2 (cKO-PT-Mfn2) on animal survival after transient bilateral renal ischemia associated with severe AKI. Fortyeight hours after ischemia, 28% of control mice survived compared with 86% of cKO-PT-Mfn2 animals (P,0.001 versus control). Although no significant differences in histologic injury score, apoptosis, or necrosis were detected between genotypes, cKO-PT-Mfn2 kidneys exhibited a 3.5-fold increase in cell proliferation restricted to the intrarenal region with Mfn2 deletion. To identify the signals responsible for increased proliferation, primary PT cells with Mfn2 deficiency were subjected to stress by ATP depletion in vitro. Compared with normal Mfn2 expression, Mfn2 deficiency significantly increased PT cell proliferation and persistently activated extracellular signal-regulated kinase 1/2 (ERK1/2) during recovery from stress. Furthermore, stress and Mfn2 deficiency decreased the interaction between Mfn2 and Ras detected by immunoprecipitation, and purified Mfn2 dose-dependently decreased Ras activity in a cell-free assay. Ischemia in vivo also reduced the Mfn2-RAS interaction and increased both RAS and p-ERK1/2 activity in the renal cortical homogenates of cKO-PT-Mfn2 mice. Our results suggest that, in contrast to its proapoptotic effects in vitro, selective PT Mfn2 deficiency accelerates recovery of renal function and enhances animal survival after ischemic AKI in vivo, partly by increasing Ras-ERK-mediated cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Gall

Wang

Bonegio

et al. 2015

Journal of the American Society of Nephrology

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“…Activation of JNK and p38 MAPK pathways results in enhanced apoptosis induced by berberine in human hepatoma and colon carcinoma cells (34,35). When the MAPKs are inhibited, the apoptosis and caspase-3 cleavage in tumor cells are abrogated (46)(47)(48). Moreover, inhibitors of MAPKs slightly increase cell viability in MDA-MB-231 cells (49).…”

Section: Discussionmentioning

confidence: 99%

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Zhao

Shi

et al. 2014

Oncology Reports

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Abstract. Breast cancer, the leading cause of cancer-related mortality worldwide in females, has high metastastic and recurrence rates. The aim of the present study was to evaluate the anti-metastatic and anticancer in situ effect of berberine hydrochloride (BER) in MDA-MB-231 cells. BER dose-dependently inhibited proliferation and the IL-8 secretion of MDA-MB-231 cells. Additional experiments revealed that the inactivation of PI3K, JAK2, NF-κB and AP-1 by BER contributed to the decreased IL-8 secretion. BER abrogated cell invasion induced by IL-8 accompanied with the downregulation of the gene expression of MMP-2, EGF, E-cadherin, bFGF and fibronectin.In addition, BER reduced cell motility but induced G2/M arrest and cell apoptosis in an IL-8-independent manner. BER modulated multiple signaling pathway molecules involved in the regulation of cell apoptosis, including activation of p38 MAPK and JNK and deactivation of JAK2, p85 PI3K, Akt and NF-κB. The enhanced cell apoptosis induced by BER was eliminated by inhibitors of p38 MAPK and JNK but was strengthened by activator of p38 MAPK. Thus, BER inhibited cell metastasis partly through the IL-8 mediated pathway while it induced G2/M arrest and promoted cell apoptosis through the IL-8 independent pathway. Apoptosis induced by BER was mediated by crosstalks of various pathways including activation of p38 MAPK and JNK pathways and inactivation of JAK2/ PI3K/NF-κB/AP-1 pathways. The results suggested that BER may be an efficient and safe drug candidate for treating highly metastatic breast cancer.

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“…Erk1 and 2 (p44 and p42) generally participate in a protein kinase cascade that regulates cell growth and differentiation as survival factors but have also been reported to be activated in apoptotic events [15,28]. Similarly to 7Me-IEITC, Cisplatin induced apoptosis of renal cells requires Erk1/2 activation [31]. Similarly to the treatment of SKOV-3 cells by 7-MeIEITC, other ITCs caused significant elevations in the phosphorylation of Erk1/2 and JNK in human prostate cancer PC-3 cells [32].…”

Section: Discussionmentioning

confidence: 99%

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

Singh¹,

Lange²,

Kim³

et al. 2008

Gynecologic Oncology

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Objective-A novel indole-ethyl isothiocyanate derivative (7Me-IEITC) was defined as a potent growth-suppressing agent to cell lines derived from ovarian cancers. Key mechanisms of the cellular response in vitro were studied and suggest a potential of 7Me-IEITC as a therapeutic drug.Methods-The viability of ovarian cancer cell lines (SKOV-3, OVCAR-3) in comparison to pancreatic and prostate cancer cell lines, primary fibroblast and immortalized trophoblasts after treatment with 7Me-IEITC was analyzed. Morphological and apoptotic responses of SKOV-3 were studied by fluorescence microscopy (DAPI staining, TUNEL assay). SKOV-3 proliferation was estimated by a standardized BrdU incorporation assay. The phosphorylation of MAP-Kinases, prosurvival factors and the activation of caspases and PARP-1 were analyzed by western blotting. Changes of the mitochondrial transmembrane-potential and in cell cycle progression were studied by FACS analysis. MAP-Kinase and caspase inhibitors were employed in cytotoxicity studies.Results-7Me-IEITC selectively reduced the viability of SKOV-3, OVCAR-3, BXPC-3 and PC-3 cells (IC50 values ≤5μM), while the viability of fibroblasts or trophoblasts remained unaffected at concentrations below 20μM. 7Me-IEITC treatment down-regulated pro-survival kinases and transcription factors (STAT-3, IKKα and NF-κB), caused rapid loss of the mitochondrial transmembrane-potential and inactivation of PARP-1 along with activation of caspases. The use of p38 MAP-Kinase-and caspase-inhibitors suppressed the cytotoxicity of the drug. 7Me-IEITC acted as an anti-proliferative agent and arrested the cell-cycle progression of SKOV-3 in G2/M phase.Conclusion-7Me-IEITC is a potent and growth-suppressing agent to cell lines derived from ovarian cancers by causing de-activation of survival signals, apoptosis, and cell-cycle arrest.

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Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells

Cited by 154 publications

References 52 publications

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

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