Long-term outcomes of CNS WHO grade 2 oligodendroglioma in adult patients: a single-institution experience.

PURPOSE: Oligodendrogliomas (ODGs) are a subtype of diffuse lower-grade gliomas with overall survival of > 10 years. This study aims to analyze long-term outcomes and identify prognostic factors in patients with WHO grade 2 ODG. METHODS: We retrospectively reviewed 138 adult patients diagnosed with 1p/19q co-deleted ODG who underwent surgical resection or biopsy between 1994 and 2021, analyzing clinical data, treatment details, and outcomes. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were utilized to identify significant prognostic factors. RESULTS: In the gross total resection (GTR) group, 63 (45.7%) underwent observation and 5 (3.6%) received postoperative treatment; in the non-GTR group, 37 (26.8%) were observed and 33 (23.9%) received postoperative treatment. The median PFS and OS were 6.8 and 18.4 years, respectively. Between adjuvant treatment and observation, there was no significant difference in PFS or OS. However, GTR or STR with less than 10% residual tumor exhibited significantly better PFS and OS compared to PR or biopsy (p = 0.022 and 0.032, respectively). Multivariate analysis revealed that contrast enhancement on MRI was associated with worse PFS (HR = 2.36, p < 0.001) and OS (HR = 5.89, p = 0.001). And the presence of seizures at presentation was associated with improved OS (HR = 0.28, p = 0.006). CONCLUSION: This study underscores favorable long-term outcomes for patients with 1p/19q co-deleted ODG WHO grade 2. Our findings indicate that the EOR plays a crucial role as a significant prognostic factor in enhancing PFS and OS outcomes in WHO grade 2 ODG.

Surgical Strategy for Petroclival Meningioma-Related Trigeminal Neuralgia: The Role of Porus Trigeminus Opening.

OBJECTIVE: Petroclival meningiomas invade Meckel's cave through the porus trigeminus, leading to secondary trigeminal neuralgia. Microsurgery and stereotactic radiosurgery (SRS) are the typical treatment options. This study investigated symptom control, outcomes, and surgical strategies for PC meningioma-induced TN. METHODS: We retrospectively analyzed 28 TN patients with PC meningiomas who underwent microsurgical nerve decompression between January 2021 and February 2023. In all patients undergoing a transpetrosal approach, the porus trigeminus was opened to enable the removal of the entire tumor within Meckel's cave. Clinical outcomes were assessed using the Barrow Neurologic Institute (BNI) pain intensity scale. Risk factors for poor TN outcomes and poor facial numbness were analyzed. RESULTS: Among 28 patients, 21 (75%) underwent the transpetrosal approach, 5 (17.9%) underwent the retrosigmoid approach, and 2 (7.1%) underwent the Dolenc approach. Following microsurgery, 23 patients (82.1%) experienced TN relief without further medication (BNI I or II). TN recurrence occurred in 2 patients (7.1%), and 3 patients (10.7%) did not achieve TN relief. Cavernous sinus invasion was significantly correlated with poor TN outcomes (P = 0.047). A history of previous SRS (P = 0.011) and upper clivus type tumor (P = 0.018) were significantly associated with poor facial numbness. CONCLUSIONS: Microsurgical nerve decompression is effective in improving BNI scores in patients with TN associated with PC meningiomas. Considering the results of our study, the opening of the porus trigeminus can be considered as a suggested procedure in the treatment of PC meningiomas, especially in cases accompanied by TN.

Exploring prognostic factors and treatment strategies for long-term survival in pleomorphic xanthoastrocytoma patients.

Pleomorphic xanthoastrocytomas (PXA) are rare, accounting for < 1% of all astrocytomas. Literature on the clinical course and treatment outcomes of PXAs is limited. The study aimed to determine prognosis and treatment strategies for PXAs. Patients who had PXAs surgery between 2000-2021 were retrospectively analyzed for demographics and radiological characteristics. Initial and salvage treatment outcomes were recorded. Overall, 40 and 9 patients had grade 2 and 3 PXAs; their 5-year progression-free survival (PFS) rates were 75.8% and 37.0%, respectively (p = 0.003). Univariate analysis revealed that strong T1 enhancement (p = 0.036), infiltrative tumor margins (p < 0.001), peritumoral edema (p = 0.003), WHO grade (p = 0.005), and gross total resection (p = 0.005) affected the PFS. Multivariate analysis revealed that the WHO grade (p = 0.010) and infiltrative tumor margins (p = 0.008) influenced the PFS. The WHO grade (p = 0.027) and infiltrative tumor margins (p = 0.027) also affected the overall survival (OS). Subgroup analysis for grade 2 PXAs revealed no significant associations between adjuvant radiation therapy and the PFS and OS. This study highlighted the heterogeneous nature of PXAs and its impact on patient prognosis. Infiltrative tumor margins emerged as a key prognostic factor. Our findings have emphasized the prognostic relevance of radiological features and the need for larger studies on comprehensive management.

Novel Chlorin e6-Curcumin Derivatives as a Potential Photosensitizer: Synthesis, Characterization, and Anticancer Activity.

Novel series of chlorin e6-curcumin derivatives were designed and synthesized. All the synthesized compounds 16, 17, 18, and 19 were tested for their photodynamic treatment (PDT) efficacy against human pancreatic cancer cell lines: AsPC-1, MIA-PaCa-2, and PANC-1. The cellular uptake study was performed in the aforementioned cell lines using fluorescence-activated cell sorting (FACS). 17, among the synthesized compounds with IC50 values of 0.27, 0.42, and 0.21 µM against AsPC-1, MIA PaCa-2, and PANC-1 cell lines, respectively, demonstrated excellent cellular internalization capability and exhibited higher phototoxicity relative to the parent Ce6. The quantitative analyses using Annexin V-PI staining revealed that the 17-PDT-induced apoptosis was dose-dependent. In pancreatic cell lines, 17 reduced the expression of the anti-apoptotic protein, Bcl-2, and increased the pro-apoptotic protein, cytochrome C, which indicates the activation of intrinsic apoptosis, the primary cause of cancer cell death. Structure-activity relationship studies have shown that the incorporation of additional methyl ester moiety and conjugation to the enone moiety of curcumin enhances cellular uptake and PDT efficacy. Moreover, in vivo PDT testing in melanoma mouse models revealed that 17-PDT greatly reduced tumor growth. Therefore, 17 might be an effective photosensitizer for PDT anticancer therapy.

Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism.

BACKGROUND: Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. RESULTS: We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. CONCLUSIONS: These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers. Video Abstract.

Correction: Yun et al. Prion Protein of Extracellular Vesicle Regulates the Progression of Colorectal Cancer. Cancers 2021, 13, 2144.

The authors wish to make the following corrections to this paper [...].

Prion Protein of Extracellular Vesicle Regulates the Progression of Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death due to its aggressive metastasis in later stages. Although there is a growing interest in the tumorigenic role of cellular prion protein (PrPC) in the process of metastasis, the precise mechanism behind the cellular communication involving prion proteins remains poorly understood. This study found that hypoxic tumor microenvironment increased the PrPC-expressing exosomes from CRC, and these exosomes regulate the CRC cell behavior and tumor progression depending on the expression of PrPC. Hypoxic exosomes from CRC cells promoted sphere formation, the expression of tumor-inducing genes, migration, invasion, and tumor growth. Furthermore, these exosomes increased endothelial permeability, migration, invasion, and angiogenic cytokine secretion. These effects were associated with PrPC expression. Application of anti-PrPC antibody with 5-fluorouracil significantly suppressed the CRC progression in a murine xenograft model. Taken together, these findings indicate that PrP-expressing exosomes secreted by hypoxic CRC cells are a key factor in the tumorigenic CRC-to-CRC and CRC-to-endothelial cell communication. Significance: These findings suggest that inhibiting PrPC in hypoxic exosomes during chemotherapy may be an effective therapeutic strategy in colorectal cancer.

Bovine milk extracellular vesicles induce the proliferation and differentiation of osteoblasts and promote osteogenesis in rats.

Bone is constantly balanced between the formation of new bone by osteoblasts and the absorption of old bone by osteoclasts. To promote bone growth and improve bone health, it is necessary to promote the proliferation and differentiation of osteoblasts. Although bovine milk is known to exert a beneficial effect on bone formation, the study on the effect of bovine milk extracellular vesicles (EVs) on osteogenesis in osteoblasts is limited. In this study, we demonstrated that bovine milk EVs promoted the proliferation of human osteogenic Saos-2 cells by increasing the expression of cell cycle-related proteins. In addition, bovine milk EVs also induced the differentiation of Saos-2 cells by increasing the expression of RUNX2 and Osterix which are key transcription factors for osteoblast differentiation. Oral administration of milk EVs did not cause toxicity in Sprague-Dawley rats. Furthermore, milk EVs promoted longitudinal bone growth and increased the bone mineral density of the tibia. Our findings suggest that milk EVs could be a safe and powerful applicant for enhancing osteogenesis. PRACTICAL APPLICATIONS: Until now, calcium and vitamin D have been prescribed to promote bone formation or to prevent bone diseases such as osteoporosis. Recently, several studies to find bioactive molecules that regulate cellular functions of osteoblasts or osteoclasts are actively underway. Milk basic proteins and lactoferrin present in milk are known to promote bone formation, but they exist in small quantities and the isolation of these proteins is complicated making mass production difficult. Recently, it has been found that milk contains large quantities of EVs, and that they promote bone formation. Studies on the effect of Milk EVs on osteoblasts during osteogenesis will help in the development of biomaterials for osteogenesis.

The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy.

Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.

Critical combination of initial markers for predicting refractory Mycoplasma pneumoniae pneumonia in children: a case control study.

BACKGROUND: It is unclear whether the responses of refractory and common Mycoplasma pneumoniae (MP) pneumonia to macrolides differ. Hence, this study aimed to identify biomarkers that may be used to distinguish refractory and common pneumonias caused by MP in children at hospital admission. METHODS: The study included 123 children divided into five groups according to infection agent and treatment protocol: Group I included those with MP infection without documented viral infection, treated with only macrolides; Group II included those with MP infection without documented viral infection, treated with a combination of macrolides and methylprednisolone; Group III included those with MP infection and documented viral infection, treated with only macrolides; Group IV included those with viral pneumonia without documented MP infection; Group V was the control group composed of admitted children without MP or a documented viral infection. These five groups were further subdivided into Groups A (including Groups I, III, IV, and V) and B (Group II) according to the responses to macrolide treatment. Concentrations of cytokines interleukin 6, interleukin 17, interleukin 18, and tumor necrosis factor-α, and lactate dehydrogenase, and ferritin of all children were evaluated, and these levels were compared among the groups. Statistical comparisons were made using Kruskal Wallis test and Mann-Whitney U test. RESULTS: Serum lactate dehydrogenase, interleukin 18, and ferritin concentrations were significantly higher in Group II than in Groups I, III, IV, and V and were significantly higher in Group B than in Group A. When the serum lactate dehydrogenase concentration was 350 IU/L or higher, the sensitivity and specificity for diagnosing refractory MP pneumonia were 73 and 80%, respectively. When the interleukin 18 level was 360 pg/mL or higher, the sensitivity and specificity for diagnosing refractory MP pneumonia were 93 and 70%, respectively. When the ferritin level was 230 pg/mL or higher, the sensitivity and specificity for diagnosing refractory MP pneumonia were 67 and 67%, respectively. CONCLUSION: These results suggest that serum lactate dehydrogenase, interleukin 18, and ferritin constitute the critical combination of biomarkers useful for predicting refractory MP pneumonia in children at hospital admission.

Brazilin selectively disrupts proximal IL-1 receptor signaling complex formation by targeting an IKK-upstream signaling components.

The ligation of interleukin-1 receptor (IL-1R) or tumor necrosis factor receptor 1 (TNFR1) induces the recruitment of adaptor proteins and their concomitant ubiquitination to the proximal receptor signaling complex, respectively. Such are upstream signaling events of IKK that play essential roles in NF-κB activation. Thus, the discovery of a substance that would modulate the recruitment of key proximal signaling elements at the upstream level of IKK has been impending in this field of study. Here, we propose that brazilin, an active compound of Caesalpinia sappan L. (Leguminosae), is a potent NF-κB inhibitor that selectively disrupts the formation of the upstream IL-1R signaling complex. Analysis of upstream signaling events revealed that brazilin markedly abolished the IL-1ß-induced polyubiquitination of IRAK1 and its interaction with IKK-γ counterpart. Notably, pretreatment of brazilin drastically interfered the recruitment of the receptor-proximal signaling components including IRAK1/4 and TRAF6 onto MyD88 in IL-1R-triggerd NF-κB activation. Interestingly, brazilin did not affect the TNF-induced RIP1 ubiquitination and the recruitment of RIP1 and TRAF2 to TNFR1, suggesting that brazilin is effective in selectively suppressing the proximal signaling complex formation of IL-1R, but not that of TNFR1. Moreover, our findings suggest that such a disruption of IL-1R-proximal complex formation by brazilin is not mediated by affecting the heterodimerization of IL-1R and IL-1RAcP. Taken together, the results suggest that the anti-IKK activity of brazilin is induced by targeting IKK upstream signaling components and subsequently disrupting proximal IL-1 receptor signaling complex formation.

New players in high fat diet-induced obesity: LETM1 and CTMP.

OBJECTIVE: Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity. MATERIALS/METHODS: To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabetic mice and genetically modified obese mice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection. RESULTS: We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obese mice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1. CONCLUSION: These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obese mice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.

PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65.

Constitutive NF-κB activation in cancer cells is caused by defects in the signalling network responsible for terminating the NF-κB response. Here we report that plant homeodomain finger protein 20 (PHF20) maintains NF-κB in an active state in the nucleus by inhibiting the interaction between PP2A and p65. We show that PHF20 induces canonical NF-κB signalling by increasing the DNA-binding activity of NF-κB subunit p65. In PHF20 overexpressing cells, the termination of tumour necrosis factor-induced p65 phosphorylation is impaired whereas upstream signalling events triggered by tumour necrosis factor are unaffected. This effect strictly depends on the interaction between PHF20 and methylated lysine residues of p65, which hinders recruitment of PP2A to p65, thereby maintaining p65 in a phosphorylated state. We further show that PHF20 levels correlate with p65 phosphorylation levels in human glioma specimens. Our work identifies PHF20 as a novel regulator of NF-κB activation and suggests that elevated expression of PHF20 may drive constitutive NF-κB activation in some cancers.

Intron-derived aberrant splicing of A20 transcript in rheumatoid arthritis.

OBJECTIVE: Aberrant splicing is one of the most significant components generating functional diversity in many pathological conditions. The objective of this study was to analyse the mutations or aberrant splicing of A20 transcript, the region encompassing the ovarian tumour (OTU) domain [which is functionally important as an inhibitor of nuclear factor (NF)-κB activation] in fibroblast-like synoviocytes (FLSs) from RA patients. METHODS: Alterations in A20 transcripts were determined through sequence analysis of 10 clones of A20 cDNA in FLSs from each of the five RA patients. The levels of aberrant A20 transcript were measured by quantitative real-time RT-PCR with primers to specifically recognize the inserted introns. The functional role of A20 and its aberrant variants were examined by analysing NF-κB luciferase reporter activity and NF-κB-dependent target gene expression. RESULTS: In RA FLSs, we discovered four novel aberrant A20 transcripts, most of which resulted from insertion of partial intron 2, intron 4 and/or deletion of exon 4. In each of these FLSs, sequence analysis revealed that these aberrant insertional sequences were flanked by consensus splice donor and acceptor sequences without nucleotide substitution, suggesting alternative splicing as the likely mutational mechanism. These variants elicited a codon frame shift by creating a premature translational stop codon, and eventually, disruption of the OTU domain (which is functionally important as an inhibitor of NF-κB activation) of A20. The expression level of aberrant A20 transcript was correlated well with persisitently enhanced status of NF-κB signalling, as evident by the phosphorylation of inhibitor of NF-κB (IκB)-α and transcription of NF-κB target genes. CONCLUSION: The results suggest that A20 inactivation by the novel aberrant splicing may contribute to RA progression by inducing persistent NF-κB activation.

Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis.

Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death.

Water extract of Cynanchi atrati Radix regulates inflammation and apoptotic cell death through suppression of IKK-mediated NF-κB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchi atrati Radix has been traditionally used as an anti-inflammatory agent to treat febrile diseases, acute urinary infection or subcutaneous pyogenic infection with invasion of the pathogenic factors. AIM OF STUDY: Nuclear factor (NF)-κB is a pleiotropic transcriptional factor of many genes involved in inflammatory and anti-apoptotic responses. To identify a novel, potent inhibitor of NF-κB signaling pathway, a plant extract library of traditional oriental medicine was screened for the capability to block the NF-κB activity in cells overexpressing toll-like receptor 4 (TLR4), and then evaluated the anti-inflammatory and pro-apoptotic functions of water extract of Cynanchi atrati Radix (WECR) in macrophages and cancer cells, respectively. MATERIALS AND METHODS: The effect of WECR on the proinflammatory mediators (inducible NO synthase [iNOS], cyclooxygenase [COX]-2), IκB-α degradation, RelA/p65 phosphorylation and caspase cleavages were measured by immunblotting. NF-κB transcriptional activity, IκB kinase (IKK) activity and nitric oxide (NO) production was measured using the luciferase assay, in vitro kinase assay and Griess reaction. RESULTS: WECR efficiently inhibited LPS-induced expression of proinflammatory mediators including iNOS and COX-2. IKK kinase activity, IκB-α degradation, nuclear translocation of RelA/p65 and NF-κB transcriptional activity induced by LPS were suppressed by WECR. Furthermore, WECR dramatically enhances the apoptotic response, as evident by the combination with tumor necrosis factor (TNF) was able to induce the cytotoxic action through caspase-dependent pathway. CONCLUSION: These results indicate that WECR has a potential to inhibit IKK-mediated NF-κB activation, and is a valuable compound for modulating inflammatory or cancerous conditions.

Apoptosis signal-regulating kinase1 is inducible by protein kinase Cδ and contributes to phorbol ester-mediated G1 phase arrest through persistent JNK activation.

Although protein kinase Cδ (PKCδ) has been suggested in the negative control of the cell cycle machinery in many types of cancer cells, its underlying mechanisms are partly understood. Here we report that the expression of apoptosis signal-regulating kinase1 (ASK1) is inducible in a PKCδ-dependent manner, and contributes to phorbol ester-induced cell cycle arrest through persistent JNK activation in breast cancer epithelial cells. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) gradually up-regulated the expression of ASK1 mRNA and protein, and subsequently enhanced its catalytic activity in MCF-7 cells. Importantly, such PMA-induced ASK1 expression was completely abolished by pretreatment of rottlerin, a specific PKCδ inhibitor or by knocking down the expression of PKCδ, while ectopic expression of a constitutively active form of PKCδ strongly up-regulated ASK1 expression. We also found that the persistent activation of mitogen-activated protein kinase, JNK in response to PMA was greatly attenuated by RNA interference-mediated knockdown of ASK1. Taken together, these results suggest that inducible expression of ASK1 by PKCδ contributes to the G1 arrest by enhancing persistent JNK signaling activation which represents a novel alternative mechanism of PKCδ-dependent cell cycle arrest and limiting proliferation of breast cancer epithelial cells.

Disruption of microtubules sensitizes the DNA damage-induced apoptosis through inhibiting nuclear factor κB (NF-κB) DNA-binding activity.

The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-κB) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-κB activation largely remains to be identified. However microtubule disrupting agents may possibly act in synergy or antagonism against apoptotic cell death in response to conventional chemotherapy targeting DNA damage such as adriamycin or comptothecin in cancer cells. Interestingly pretreatment of microtubule disrupting agents (colchicine, vinblastine and nocodazole) was observed to lead to paradoxical suppression of DNA damage-induced NF-κB binding activity, even though these could enhance NF-κB signaling in the absence of other stimuli. Moreover this suppressed NF-κB binding activity subsequently resulted in synergic apoptotic response, as evident by the combination with Adr and low doses of microtubule disrupting agents was able to potentiate the cytotoxic action through caspase-dependent pathway. Taken together, these results suggested that inhibition of microtubule network chemosensitizes the cancer cells to die by apoptosis through suppressing NF-κB DNA binding activity. Therefore, our study provided a possible anti-cancer mechanism of microtubule disrupting agent to overcome resistance against to chemotherapy such as DNA damaging agent.