Phosphorylation of IκBα at Serine 32 by T-lymphokine-activated Killer Cell-originated Protein Kinase Is Essential for Chemoresistance against Doxorubicin in Cervical Cancer Cells

Park, Jung-Hwan; Yoon, Dae Sung; Choi, Hye Jin; Hahm, Dae Hyun; Oh, Sang Muk

doi:10.1074/jbc.m112.422170

Cited by 33 publications

(33 citation statements)

References 41 publications

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“…In addition, Akt also activates IKKα (41)(42)(43). On the other hand, PBK/TOPK directly interacts with and phosphorylates IκBα, leading to NF-κB activation (25). Our results revealed that HI-TOPK-032 suppressed the phosphorylation of IKKα/β and IκBα, suggesting that PBK/TOPK seems to activate NF-κB through direct phosphorylation of IκBα or indirect activation of the PI3K-Akt-IKK signaling pathway by inactivation of PTEN.…”

Section: Discussionmentioning

confidence: 72%

Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma

2018

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Adult T‑cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV‑1)-infected T‑cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T‑lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT‑PCR. We found that PBK/TOPK was upregulated and phosphorylated in HTLV‑1-transformed T‑cell lines and ATLL‑derived T‑cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV‑1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI‑TOPK‑032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose‑dependent manner. By contrast, the effect of HI‑TOPK‑032 on PBMCs was less pronounced. Treatment with HI‑TOPK‑032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI‑TOPK‑032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase‑3, -8 and -9, and an increase in the sub‑G1 cell population and APO2.7-positive cells. Moreover, HI‑TOPK‑032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia‑1 (Mcl‑1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein‑1 signaling pathways. In vivo, the administration of HI‑TOPK‑032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.

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Section: Discussionmentioning

confidence: 72%

Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma

2018

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“…Several reports have demonstrated the potential of TOPK to attenuate apoptosis and enhance antioxidant capacity in cancer cell lines. For example, TOPK has been shown to inhibit As 3+ -induced apoptosis through induction of histone H2AX phosphorylation [16], stable TOPK knockdown increases apoptosis in human colon cancer cells (HCT116) and breast adenocarcinoma cells (MCF-7) via interaction with p53 [17], and doxorubicin-mediated apoptosis in human epithelial carcinoma cell HeLa was found to be noticeably increased after TOPK knockdown by IjBa phosphorylation [18]. In addition, TOPK was shown to prevent apoptosis induced by UVB in RPMI7951 human melanoma cells through phosphorylation of Prx1 and reduced H 2 O 2 accumulation [8].…”

Section: Discussionmentioning

confidence: 99%

Activation of T‐LAK‐cell‐originated protein kinase‐mediated antioxidation protects against focal cerebral ischemia–reperfusion injury

et al. 2014

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T-LAK-cell-originated protein kinase (TOPK), a MAPKK-like kinase, is crucial for neural progenitor cell proliferation; however, the function of TOPK and the molecular mechanism underlying cerebral ischemia-reperfusion injury remains unknown. Therefore, we investigated the role of TOPK in experimental stroke. Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO) and reperfusion, and TOPK small interfering RNA (siRNA) was delivered by intracerebroventricular injection at the beginning of MCAO. After TOPK overexpression and H 2 O 2 stimulation in PC12 neuronal cells, antioxidative proteins, apoptosis-related proteins and signal pathways were detected by western blot analysis, the levels of the peroxidation products (malondialdehyde and 3-nitrotyrosine) were measured with ELISA. Phosphorylation of TOPK was increased in rat cortical neurons following tMCAO. TOPK overexpression in PC12 cells augmented levels of antioxidative proteins (peroxiredoxin 1 and 2, heme oxygenase 1 and manganese superoxide dismutase), as well as total superoxide dismutase activity, along with inhibition of malondialdehyde and 3-nitrotyrosine upon H 2 O 2 stimulation. TOPK overexpression increased cell viability and reduced expression of caspase 3 and caspase 12 in PC12 cells in response to H 2 O 2 . The p-ERK level was increased by TOPK overexpression, and antioxidative protection afforded by TOPK was abolished by blocking the extracellular signal-regulated kinase pathway in PC12 cells. TOPK siRNA increased the infarct volume and reduced total superoxide dismutase activity in the cortex in vivo after MCAO. These data reveal that activating TOPK confers neuroprotection against focal cerebral ischemiareperfusion injury by antioxidative function, in part through activation of the extracellular signal-regulated kinase pathway.Abbreviations 3-NT, 3-nitrotyrosine; Akt, protein kinase B; ERK, extracellular signal-regulated kinase; HO-1, heme oxygenase 1; MDA, malondialdehyde; Prx-1, peroxiredoxin 1; siRNA, small interfering RNA; tMCAO, transient middle cerebral artery occlusion; TOPK, T-LAK-cell-originated protein kinase; TTC, 2,3,5-triphenyltetrazolium chloride.

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“…Recently, fucoidan was reported to directly interact with TOPK kinase and inhibit its kinase activity (23). Furthermore, TOPK directly interacted with and phosphorylated IκBα (24). Therefore, we investigated whether fucoidan influenced the activity of TOPK, an upstream kinase of IκBα.…”

Section: Fucoidan Induces Downregulation Of Cdk4 Cdk6 Bcl-xlmentioning

confidence: 99%

In vitro and in vivo anti-primary effusion lymphoma activities of fucoidan extracted from Cladosiphon okamuranus Tokida

Ishikawa

Mori

2017

Oncology Reports

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Primary effusion lymphoma (PEL) caused by Kaposi's sarcoma-associated herpesvirus (KSHV) is characterized by lymphomatous effusion in body cavities and poor prognosis. There is still no effective treatment for PEL. Fucoidan, a major sulfated polysaccharide isolated from brown seaweeds, has an attractive array of bioactivities such as cancer inhibition. However, the effects of fucoidan on PEL cells remain unclear. We investigated the anti-PEL effects of fucoidan obtained from Cladosiphon okamuranus Tokida cultivated in Okinawa. Fucoidan dose-dependently inhibited the proliferation of KSHV-infected PEL cell lines, and provoked G1 cell cycle arrest, which was accompanied by CDK4 and CDK6 downregulation. Fucoidan also induced apoptosis of PEL cells through caspase-3, -8 and -9 activation; this occurred partly through the downregulation of anti-apoptotic Bcl-xL, Mcl-1 and XIAP proteins. Fucoidan also suppressed nuclear factor-κB, activator protein-1 (AP-1), and T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling pathways through inhibition of phosphorylation of IκBα and TOPK, and the expression of AP-1 family proteins, JunB and JunD. Oral administration of fucoidan effectively inhibited the development of PEL cells and ascites in a xenograft SCID mouse model, with minimal serious adverse effects. Notably, native fucoidan exhibited a more efficient anti-PEL effect than nanoparticle fucoidan. These preclinical findings highlight the anti-PEL actions of fucoidan, suggesting it could be potentially useful for the prevention and treatment of PEL.

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Phosphorylation of IκBα at Serine 32 by T-lymphokine-activated Killer Cell-originated Protein Kinase Is Essential for Chemoresistance against Doxorubicin in Cervical Cancer Cells

Cited by 33 publications

References 41 publications

Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma

Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma

Activation of T‐LAK‐cell‐originated protein kinase‐mediated antioxidation protects against focal cerebral ischemia–reperfusion injury

In vitro and in vivo anti-primary effusion lymphoma activities of fucoidan extracted from Cladosiphon okamuranus Tokida

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