Posts

Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine

Image
Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine ABSTRACT While sequencing studies have provided an improved understanding of the genetic landscape of head and neck squamous cell carcinomas (HNSCC), there remains a significant lack of genetic data derived from non-Caucasian cohorts. Additionally, there is wide variation in HNSCC incidence and mortality worldwide both between and within various geographic regions. These epidemiologic differences are in part accounted for by varying exposure to environmental risk factors such as tobacco, alcohol, high risk human papilloma viruses and betel quid. However, inherent genetic factors may also play an important role in this variability. As limited sequencing data is available for many populations, the involvement of unique genetic factors in HNSCC pathogenesis from epidemiologically diverse groups is unknown. Here, we review current knowledge about the epidemiologic, environmenta
Post a Comment
Read more

Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells

Image
Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells ABSTRACT Radioimmunotherapy (RIT) is an emerging treatment option for non-Hodgkin lymphoma (NHL) producing higher overall response and complete remission rates compared with unlabelled antibodies. However, the majority of patients treated with conventional or myeloablative doses of radiolabelled antibodies relapse. The development of RIT with alpha-emitters is attractive for a variety of cancers because of the high linear energy transfer (LET) and short path length of alpha-radiation in human tissue, allowing higher tumour cell kill and lower toxicity to healthy tissues. In this study, we investigated the molecular effects of the alpha-emitter Bi-213 labelled to anti-CD20 antibodies ([Bi- 213 ]anti-CD20) on cell cycle and cell death in sensitive and radio-/chemoresistant NHL cells. [Bi- 213 ]anti-CD20 induced apoptosis, activated caspase-3, caspase-2 and cas
Post a Comment
Read more

Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors. Zoya N. Demidenko. Mikhail V. Blagosklonny

Depletion of Mutant p53 and Cytotoxicity of Histone Deacetylase Inhibitors Abstract Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with histone deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, histone deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific
Post a Comment
Read more

Complementation of two mutant p53: Implications for loss of heterozygosity in cancer. Zoya N. Demidenko. Mikhail V. Blagosklonny

Complementation of two mutant p53: Implications for loss of heterozygosity in cancer Abstract Remarkably, a cancer cell rarely possesses two mutant p53 proteins. Instead, mutation of one allele is usually associated with loss of the second p53 allele. Why do not two mutant p53 co‐exist? We hypothesize that two different p53 may complement each other, when expressed at equal levels. By titrating trans‐deficient and DNA‐binding‐deficient p53 in cells with mutant p53 and by co‐transfecting distinct mutant p53 in p53‐null cells, we demonstrated activation of p53‐dependent transcription. We suggest that, due to complementation of two mutant p53, cancer cells need to delete the second p53 allele rather than mutate it. 1 Introduction Inactivation of the p53 tumor suppressor is the most common alteration in human cancer  [ 1 ,  2 ] . Usually, mutant p53 is associated with the loss of the second p53 allele, known as loss of heterozygosity (LOH)  [ 3 ] . Wild‐type (wt) p53, a transcription facto
Post a Comment
Read more

Accumulation of hypoxia-inducible factor-1α is limited by transcription-dependent depletion. Zoya N Demidenko. Mikhail V Blagosklonny

Accumulation of hypoxia-inducible factor-1 α  is limited by transcription-dependent depletion Abstract In the presence of oxygen and iron, hypoxia-inducible factor (HIF-1 α ) is rapidly degraded via the prolyl hydroxylases (PHD)/VHL pathways. Given striking similarities between p53 and HIF-1 α  regulation, we previously suggested that HIF-1 transcriptionally initiates its own degradation and therefore inhibitors of transcription must induce HIF-1 α . Under normoxia, while inducing p53, inhibitors of transcription did not induce HIF-1 α . Under hypoxia or low iron (DFX), inhibitors of transcription dramatically super-induced HIF-1α. Removal of inhibitors resulted in outburst of the HIF-1-dependent transcription followed by depletion of HIF-1 α . Although hypoxia/DFX induced PHD3, we excluded the PHD/VHL pathway in the regulation of HIF-1 α  under hypoxia/DFX. The transcription-dependent degradation of HIF-1 α  under hypoxia occurs via the proteasome and is accelerated by protein acetyla
Post a Comment
Read more

Paradoxical suppression of cellular senescence by p53. Zoya N. Demidenko. Mikhail V. Blagosklonny

Paradoxical suppression of cellular senescence by p53 Abstract The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology). p53 can also cause reversible arrest without senescent morphology, which has usually been interpreted as failure of p53 to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultan
Post a Comment
Read more

Autophagic activity dictates the cellular response to oncogenic RAS

Autophagic activity dictates the cellular response to oncogenic RAS Abstract RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2 (Δ3/Δ3)  mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, A
Post a Comment
Read more