BAX
Apoptosis regulator BAX (Bcl-2-like protein 4) (Bcl2-L-4) [BCL2L4]
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Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL-X and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor-bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.
Keywords
- ABT-263
- BCL-XL
- chemotherapy
- radiation
- senescence
- senolytic
The impact of low-dose ionizing radiation (IR) on the human brain has recently attracted attention due to the increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in the hippocampus. Female B6C3F1 mice were exposed to total body irradiation with 0 (control), 0.063, 0.125, or 0.5 Gy. Quantitative label-free proteomic analysis of the hippocampus was performed after 24 months. CREB signaling and CREB-associated pathways were affected at all doses. The lower doses (0.063 and 0.125 Gy) induced the CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory, reducing the number of activated microglia. In contrast, induction of activated microglia and reactive astroglia was found at 0.5 Gy, suggesting increased inflammation and astrogliosis, respectively. The apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers were increased only at the highest dose. Since the activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. The response to 0.5 Gy resembles alterations found in healthy aging and thus may represent radiation-induced accelerated aging of the brain.
Keywords
- CREB signaling
- aging
- brain
- hippocampus
- ionizing radiation
- label-free proteomics
The present study aimed to investigate the effects of vitamin D3 in the epididymal sperm cells of D-gal-induced aged rats. It is well known that during aging sperm quality and quantity declines and leads to age-related infertility problems in males. The results of the present study showed that there were elevated levels of oxidative stress and poor DNA integrity of sperm of aged rats. The expression of BCL2 also showed a significant decline in the sperm of aged rats, however, the expression of BAX and active caspase-3 did not show significant change compared with the control group. The treatment of vitamin D3 at lower doses to aged rats showed increased expression of BAX and active caspase-3 in the sperm, this finding suggests that increased apoptosis may be responsible for removal of poor quality sperm during aging. Vitamin D3 treatment at both doses showed improvement in the oxidative stress and DNA integrity in the sperm of aged rats. We also investigated the expression of AGER, visfatin, and HSPA1A in the epididymal sperm. It has been found that expression of AGER, visfatin, and HSPA1A increased in the sperm aged rats and vitamin D3 treatments at both doses decreased its expression. Thus, it might be suggested that during aging vitamin D3 treatment would be important for managing the sperm quality by regulating the apoptosis, antioxidant system and DNA integrity via modulation of visfatin and HSPA1A.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Apoptosis
- Cholecalciferol
- Epididymis
- Male
- Rats
- Rats, Wistar
- Spermatozoa
Keywords
- aging
- apoptosis
- oxidative stress
- sperm
Sucrose nonfermenting AMPK-related kinase (SNARK) is a member of the AMPK family of kinases and has been implicated in the regulation of critical metabolic processes. Recent findings demonstrate that SNARK has an important role in the maintenance of muscle mass with age. Loss of skeletal muscle mass (cachexia) is a key problem for cancer patients. Thus, based on our previous findings with aging, we hypothesized that SNARK would play a role in regulating muscle mass under conditions of cancer cachexia. To test this hypothesis, Lewis Lung Carcinoma tumor cells or vehicle were injected subcutaneously in the right flank of wild type mice, muscle-specific transgenic mice expressing inactive SNARK mutant (SDN) or muscle-specific transgenic mice overexpressing wild-type SNARK (SWT). All tumor-bearing mice presented muscle wasting compared to vehicle-injected mice. However, SDN tumor-bearing mice had more pronounced atrophy compared to wild-type and SWT tumor-bearing mice. Histological analysis confirmed muscle atrophy in tumor-bearing mice, and SDN tumor-bearing mice exhibited a significantly smaller skeletal muscle cross-sectional area than wild-type and SWT tumor-bearing mice. Moreover, SDN tumor-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared to other groups.Thus, lack of SNARK in skeletal muscle aggravates cancer-induced skeletal muscle wasting. These findings uncover a role for SNARK in the maintenance of skeletal muscle mass under cachexia conditions.
MeSH Terms
- AMP-Activated Protein Kinases
- Animals
- Apoptosis
- Cachexia
- Carcinoma, Lewis Lung
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Muscle, Skeletal
- Muscular Atrophy
- Protein-Serine-Threonine Kinases
- Sucrose
Keywords
- AMPK
- Aging
- Cancer cachexia
- Muscle atrophy
Modulated electro-hyperthermia (mEHT), a noninvasive complementary treatment of human chemo- and radiotherapy, can generate selective ~42°C heat in cancer due to elevated glycolysis (Warburg-effect) and electric conductivity in malignant tissues. Here we tested the molecular background of mEHT and its combination with doxorubicin chemotherapy using an in vitro model. C26 mouse colorectal adenocarcinoma cultures were mEHT treated at 42°C for 2 × 60 minutes (with 120 minutes interruption) either alone or in combination with 1 µmol/L doxorubicin (mEHT Dox). Cell stress response, apoptosis, and cell cycle regulation related markers were detected using qPCR and immunocytochemistry supported with resazurin cell viability assay, cell death analysis using flow-cytometry and clonogenic assay. Cell-stress by mEHT alone was indicated by the significant upregulation and release of hsp70 and calreticulin proteins 3 hours posttreatment. Between 3 and 9 hours after treatment significantly reduced anti-apoptotic XIAP, BCL-2, and BCL-XL and elevated pro-apoptotic BAX and PUMA, as well as the cyclin dependent kinase inhibitor p21 mRNA levels were detected. After 24 hours, major elevation and nuclear translocation of phospho-p53(Ser15) protein levels and reduced phospho-Akt(Ser473) levels were accompanied by a significant caspase-3-mediated programmed cell death response. While mEHT dominantly induced apoptosis, Dox administration primarily led to tumor cell necrosis, and both significantly reduced the number of tumor progenitor colonies 10 days post-treatment. Furthermore, mEHT promoted the uptake of Dox by tumor cells and the combined treatment additively reduced tumor cell viability and augmented cell death near to synergy. In C26 colorectal adenocarcinoma mEHT-induced irreversible cell stress can activate both caspase-dependent apoptosis and p21 mediated growth arrest pathways, likely to be driven by the upregulated nuclear p53 protein. Elevated phospho-p53(Ser15) might contribute to p53 escape from mdm2 control, which was further supported by reduced phospho-Akt(Ser473) protein levels. In combinations, mEHT could promote the uptake and significantly potentiate the cytotoxic effect of doxorubicin.
MeSH Terms
- Animals
- Cell Cycle
- Cell Line, Tumor
- Cell Survival
- Colorectal Neoplasms
- Combined Modality Therapy
- Doxorubicin
- Gene Expression Regulation, Neoplastic
- Hyperthermia, Induced
- Mice
- Models, Biological
- Phosphorylation
- Signal Transduction
- Tumor Suppressor Protein p53
Keywords
- caspase dependent apoptosis
- colorectal cancer
- doxorubicin potentiation
- modulated electro-hyperthermia
- p53 and p21waf1 upregulation
- tumor senescence
Senescent cells are characterized by their resistance to apoptosis, and upon their long-term survival senescent cells affect tissue function and eventually become deleterious to the organism. Thus, far, it has been gradually accepted that clearance of these senescent cells could reduce tissue dysfunction. This study aimed to investigate biological effects of tetrahedral DNA nanostructures (TDNs) on senescent cells. The results revealed a different biological effect of TDNs, and their clearance effect on senescent cells. TDNs can induce phenotypic changes in senescent cells, suppressing antiapoptotic BCL-2 family proteins and upregulating BAX, a BCL-2 family proapoptotic protein, to influence the expression levels and function of downstream proteins. Consequently, cytochrome C releasing promoted cleavage-mediated activation of pro-caspase-3 and its nuclear translocation from the cytoplasm to mediate apoptosis. The present results provide a foundation for further studies on the application of TDNs in studies on aging.
MeSH Terms
- Apoptosis
- Cellular Senescence
- Cytochromes c
- DNA
- Dermis
- Fibroblasts
- Humans
- Nanostructures
- Up-Regulation
- bcl-2-Associated X Protein
Keywords
- apoptosis
- caspase
- clearance
- senescence
- tetrahedral DNA nanostructures
{{medline-entry |title=Premature placental aging in term small-for-gestational-age and growth-restricted fetuses. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30125412 |abstract=To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3 and 9 percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3 percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2 method) were determined in placental samples collected at birth and compared between the three groups. Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2 , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2 , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2 , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2 , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley