Synergism of ursolic acid and cisplatin promotes apoptosis and enhances growth inhibition of cervical cancer cells via suppressing NF-κB p65

Alafate

et al. 2020

Preprint

Abstract Background Lower-grade gliomas (LGGs) are grade II/III gliomas based on the WHO classification with significant genetic heterogeneity and clinical properties. Traditional histological classification of gliomas has been challenged by the improvement of molecular stratification, however, the reproducibility and diagnostic accuracy of LGGs classification remain poor. Methods In this study, we derived all relevant data of LGGs including TCGA and CGGA databases from official websites. Bioinformatic analyses unveiled the clinical significance of FABP5 and its potential downstream targets. IHC, qRT-PCR and western blot assays were further conducted to validate those bioinformatic findings. Moreover, lentiviral transduction assays were performed to evaluate the function of FABP5 in patient-derived cell lines. Results We identified fatty acid binding protein 5 (FABP5) as one of the most enriched genes in malignant LGGs and elevated FABP5 revealed severe outcomes in LGGs. Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, migration, invasion and TMZ resistance, contrarily, the malignancies of LGGs were enhanced by exogenous overexpression of FABP5. Mechanistically, epithelial-mesenchymal transition (EMT) was correlated to FABP5 expression in LGGs and tumor necrosis factor α (TNFα)-dependent NF-κB signaling was involved in this process. Furthermore, FABP5 induced phosphorylation of inhibitor of nuclear factor kappa-B kinase α (IKKα) thus activated nuclear factor kappa-B (NF-κB) signaling. Conclusion Taken together, our study indicated that FABP5 enhances malignancies of LGGs through canonical activation of NF-κB signaling, which could be used as individualized prognostic biomarker and potential therapeutic target of LGGs.

Section: Discussionmentioning

confidence: 99%

FABP5 enhances malignancies of lower-grade gliomas via canonical activation of NF-κB signaling

Alafate

et al. 2020

Preprint

“…NF-κB p65 is a well-recognized anti-apoptotic transcription factor and abnormal expression or activation of NF-κB p65 has been found in multiple types of malignant cancers such as cervical cancer, esophageal squamous cancer, ovarian cancer, breast cancer and glioma et al [13,[26][27][28][29]. NF-κB promotes tumorigenesis and therapy resistance mainly through induction of master transcription factors including signal transducer and activator of transcription 3 (STAT3) and TAZ [30].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor I A Promotes Temozolomide Resistance in Glioblastoma via Transcriptional Regulation of Nuclear Factor κB Pathway

Zuo

et al. 2019

Preprint

Background: Glioma is one of the most common primary brain tumors in human with severe mortality based on its therapy resistance and recurrence. Many molecular pathways and regulation factors have been proved to be required for GBM growth and therapy resistance, however, the underlying molecular mechanisms still remains unclear. Methods: Nuclear factor I-A (NFIA) was identified as a key candidate kinase encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, western blotting and in vivo xenograft models followed by temozolomide (TMZ) resistant U87 cell induction. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. At last, lentiviral silencing of NFIA was used to explore the potential downstream targets for NFIA in acquired TMZ resistance in GBM.. Results: We identified NFIA was the most correlated gene for TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated to adverse outcomes of glioma patients especially in GBM patients. Moreover, NFIA was functionally required for TMZ resistance of U87 cells while suppression of NFIA via lentivirus infection reduced cell proliferation, tumorigenesis as well as resistance to TMZ in GBM cells. Lastly, NFIA promoted acquired TMZ resistance in GBM via transcription activity thus regulated the expression of nuclear factor κB (NF-kB). Conclusions: Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to the acquired TMZ resistance in GBM, indicating that NFIA-NF-κB axis could be a new therapeutic target for TMZ resistant GBM.

Oxidative Medicine and Cellular Longevity

“…I κ B α is phosphorylated and decomposed with the activation of IKK β , and NF- κ B dimer released from the cytoplasmic NF- κ B-I κ B complex causes transcription in the nucleus [5, 7, 8]. In various diseases, NF- κ B dysregulation in the canonical pathway has been confirmed, and the dysregulation of NF- κ B is also activated by radiation exposure [9, 10, 12, 24]. In the present study, the administration of IMD-0354 to X-irradiated mice significantly suppressed the NF- κ B in bone marrow cells on days 8 and 18 and in spleen cells on day 8 after X-irradiation (Figures 4, 6, and 7).…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated I κ B α is then ubiquitinated and becomes the target of degradation by the 26S proteasome, and NF- κ B detached from I κ B α migrates into the nucleus and binds to DNA, resulting in the gene expression of inflammatory proteins, antiapoptotic proteins, or cell-adhesion molecules [5–8]. Since NF- κ B is constitutively activated in many cancer cells, several studies have evaluated substances targeting NF- κ B as anticancer agents [9, 10].…”

Section: Introductionmentioning

confidence: 99%

IKKβ Inhibitor IMD-0354 Attenuates Radiation Damage in Whole-body X-Irradiated Mice

Waga

Yamaguchi

Miura

et al. 2019

Nuclear factor-kappa B (NF-κB) transcription factor plays a critical role in regulating radiation-induced inflammatory and immune responses. Intracellular reactive oxygen species generation induces the activation of NF-κB via the inhibitor of κB (IκB) kinase (IKK) complex signaling. Previous studies have reported that the inhibition of IKK-driven NF-κB activation offers a therapeutic strategy for managing inflammatory disorders and various cancers, but it has additionally been reported that treatment targeting NF-κB also shows a radioprotective effect. IMD-0354 is an IKKβ inhibitor that blocks IκBα phosphorylation in the NF-κB pathway. This compound is known to exert anti-inflammatory and antitumor effects, but its radioprotective effects are unclear. Therefore, in the present study, we examined whether or not IMD-0354 has a mitigative effect on radiation-induced damages in mice. IMD-0354 was dissolved in soybean oil and subcutaneously administered to C57BL/6J Jcl mice for 3 consecutive days after 7 Gy of whole-body X-irradiation. The survival rate on day 30 and the NF-κB p65 and IκBα in bone marrow and spleen cells based on flow cytometry were assessed. IMD-0354 administration significantly suppressed the lethality induced by whole-body X-irradiation, and the survival rate increased by 83%. The NF-κB p65 and IκBα in bone marrow and spleen cells were significantly lower in IMD-0354-treated mice than in irradiated mice, suggesting that the IKKβ inhibitor IMD-0354 exerts a radiomitigative effect by suppressing the NF-κB.