Mikhail Blagosklonny and Zoya N. Demidenko

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

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

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

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

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

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

Circadian changes in long noncoding RNAs in the pineal gland Abstract Long noncoding RNAs (lncRNAs) play a broad range of biological roles, including regulation of expression of genes and chromosomes. Here, we present evidence that lncRNAs are involved in vertebrate circadian biology. Differential night/day expression of 112 lncRNAs (0.3 to >50 kb) occurs in the rat pineal gland, which is the source of melatonin, the hormone of the night. Approximately one-half of these changes reflect nocturnal increases. Studies of eight lncRNAs with 2- to >100-fold daily rhythms indicate that, in most cases, the change results from neural stimulation from the central circadian oscillator in the suprachiasmatic nucleus (doubling time = 0.5–1.3 h). Light exposure at night rapidly reverses (halving time = 9–32 min) levels of some of these lncRNAs. Organ culture studies indicate that expression of these lncRNAs is regulated by norepinephrine acting through cAMP. These findings point to a dynamic r

Hypoxia suppresses conversion from proliferative arrest to cellular senescence Abstract Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, β-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exp

Recent discoveries in the cycling, growing and aging of the p53 field Abstract The P53 gene and it product p53 protein is the most studied tumor suppressor, which was considered as oncogene for two decades until 1990. More than 60 thousand papers on the topic of p53 has been abstracted in Pubmed. What yet could be discovered about its role in cell death, growth arrest and apoptosis, as well as a mediator of the therapeutic effect of anticancer drugs. Still during recent few years even more amazing discoveries have been done. Here we review such topics as suppression of epigenetic silencing of a large number of non-coding RNAs, role of p53 in suppression of the senescence phenotype, inhibition of oncogenic metabolism, protection of normal cells from chemotherapy and even tumor suppression without apoptosis and cell cycle arrest.  https://www.aging-us.com/article/100529 oncotarget predatory Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncot