Table of Contents

Volume 10, Issue 24

  December 15, 2011

  Pages 4173 - 4342

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SPECIAL FEATURE ON INTERDISCIPLINARY RESEARCH

Open Access Article

Adult stem cells: Simply a tool for regenerative medicine or an additional piece in the puzzle of human aging?

James R. Tollervey and Victoria V. Lunyak
Pages 4173 - 4176
http://dx.doi.org/10.4161/cc.10.24.18832
Abstract | PDF

Adult stem cells have taken center stage in current research related to regenerative medicine and pharmacogenomic studies seeking new therapeutic interventions. As we learn more about these cells, it is becoming apparent that the next big leap in our understanding of adult stem cell biology and adult stem cell aging will depend on the integration of approaches from various disciplines. Major advances and technological breakthroughs at the crossroad of fields such as biomaterials, genomics, epigenomics, and proteomics will enable the design of better tools to model human diseases, and warrant safe usage of adult stem cells in the clinic.

Open Access Article

The Buck Institute: An inside look

Brian K. Kennedy
Pages 4177 - 4178
http://dx.doi.org/10.4161/cc.10.24.18834
PDF

Open Access Article

Prospects and challenges for the use of stem cell technologies to develop novel therapies for Parkinson disease

Shankar J. Chinta and Julie K. Andersen
Pages 4179 - 4180
http://dx.doi.org/10.4161/cc.10.24.18835
PDF

Open Access Article

Global profiling and relative quantifiction of histones, histone PTMs and histone-modifying enzymes in mesenchymal stem cells using LC-MS/MS and a novel PerfectPair mass difference algorithm

Mary F. Lopez, David Sarracino, Michael Athanas, Bryan Krastins, Amol Prakash and Alejandra Garces
Pages 4181 - 4183
http://dx.doi.org/10.4161/cc.10.24.18836
PDF

Open Access Article

Biosprays: From the biomedical to the clinical sciences

Suwan N. Jayasinghe
Pages 4184 - 4185
http://dx.doi.org/10.4161/cc.10.24.18837
PDF

Open Access Article

Computational approaches for the transcriptomics, proteomics and epigenetic analysis in adult stem cells

I. King Jordan
Page 4186
http://dx.doi.org/10.4161/cc.10.24.18838
PDF

Open Access Article

The secret lives of stem cells: Unraveling the molecular basis of stem cell aging

Kyung-Sun Kang
Page 4187
http://dx.doi.org/10.4161/cc.10.24.18839
PDF

Open Access Article

Orphan technology: Unfunded early-stage bioscience is dropped off at the firehouse

Ronald Landes
Page 4188
http://dx.doi.org/10.4161/cc.10.24.18840
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EDITORIALS: CELL CYCLE FEATURES

The ultimate transformers: Mesenchymal stem cells

Nicole Noren Hooten and Michele K. Evans
Pages 4189 - 4190
http://dx.doi.org/10.4161/cc.10.24.18490
Abstract | PDF

Comment on: Jiang SS, et al. Aging 2011; 3:672-84

A conundrum in mammalian hematopoietic stem cell polarity

Amitava Sengupta and Jose A. Cancelas
Pages 4191 - 4192
http://dx.doi.org/10.4161/cc.10.24.18361
Abstract | PDF

Comment on: Sengupta A, et al. Proc Natl Acad Sci USA 2011; 108:9957-62.

E2F1 at the crossroad of proliferation and oxidative metabolism

Lluis Fajas and Jean-Sébastien Annicotte
Pages 4193 - 4194
http://dx.doi.org/10.4161/cc.10.24.18362
Abstract | PDF

Comment on: Blanchet E, et. Nat Cell Biol 2011; 13:1146-52.

Coordinating cell cycle progression via cyclin specificity

Felicia Walton Pagliuca, Mark O. Collins and Jyoti S. Choudhary
Pages 4195 - 4196
http://dx.doi.org/10.4161/cc.10.24.18395
Abstract | PDF

Comment on: Pagliuca FW, et al. Mol Cell 2011; 43:406-17.

Chromatin regulation by CRL4 E3 ubiquitin ligases: CUL4B targets WDR5 ubiquitylation in the nucleus

Tadashi Nakagawa and Yue Xiong
Pages 4197 - 4198
http://dx.doi.org/10.4161/cc.10.24.18407
Abstract | PDF

Comment on: Nakagawa T, et al. Mol Cell. 2011; 43:381-91.

Dominant-negative isoforms of Tcf/Lef proteins in development and disease

Tomas Vacik and Greg Lemke
Pages 4199 - 4200
http://dx.doi.org/10.4161/cc.10.24.18465
Abstract | PDF

Comment on: Vacik T, et al. Genes Dev 2011; 25:1783-95.

Aging, sarcopenia and store-operated calcium entry: A common link?

Marco Brotto
Pages 4201 - 4202
http://dx.doi.org/10.4161/cc.10.24.18645
Abstract | PDF

Comment on: Thornton AM, et al. Aging 2011; 3:621-34.




CELL CYCLE NEWS & VIEWS

Open Access Article

Beyond tumor suppression: p53 controls blastocyst implantation

Shalom Madar, Ido Goldstein, Ortal Neeman and Varda Rotter
Page 4203
http://dx.doi.org/10.4161/cc.10.24.18412
Abstract | PDF

Comment on: Sohr S, et al. Cell Cycle 2011; 10:3758-67.

Open Access Article

Bridging the gaps: From risk loci via non-coding RNAs to gene networks and prostate cancer phenotypes

Ian G. Mills
Page 4204
http://dx.doi.org/10.4161/cc.10.24.18411
Abstract | PDF

Comment on: Glinskii AB, et al. Cell Cycle 2011; 10:3571-97.

Open Access Article

More on the pro-fertility activity of p53: The blastocyst side

Roberto Mantovani
Page 4205
http://dx.doi.org/10.4161/cc.10.24.18413
Abstract | PDF

Comment on: Sohr S, et al. Cell Cycle 2011; 10:3758-67.

Open Access Article

Rapamycin for life: A step to immortality

Zoya N. Demidenko
Page 4206
http://dx.doi.org/10.4161/cc.10.24.18562
Abstract | PDF

Comment on: Anisimov VN, et al. Cell Cycle 2011; 10:4230-6.

Open Access Article

Dissimilar DNA binding by p53 in normal and tumor-derived cells

William A. Freed-Pastor and Carol Prives
Page 4207
http://dx.doi.org/10.4161/cc.10.24.18723
Abstract | PDF

Comment on: Krassimira Botcheva, et al. Cell Cycle 2011; 10:4237-49.




PERSPECTIVES

Open Access Article

Energy transfer in "parasitic" cancer metabolism: Mitochondria are the powerhouse and Achilles' heel of tumor cells

Ubaldo E. Martinez-Outschoorn, Richard G. Pestell, Anthony Howell, Mark L. Tykocinski, Fnu Nagajyothi, Fabiana S. Machado, Herbert B. Tanowitz, Federica Sotgia and Michael P. Lisanti
Pages 4208 - 4216
http://dx.doi.org/10.4161/cc.10.24.18487
Abstract | PDF

It is now widely recognized that the tumor microenvironment promotes cancer cell growth and metastasis via changes in cytokine secretion and extracellular matrix remodeling. However, the role of tumor stromal cells in providing energy for epithelial cancer cell growth is a newly emerging paradigm. For example, we and others have recently proposed that tumor growth and metastasis is related to an energy imbalance. Host cells produce energy-rich nutrients via catabolism (through autophagy, mitophagy, and aerobic glycolysis), which are then transferred to cancer cells to fuel anabolic tumor growth. Stromal cell-derived L-lactate is taken up by cancer cells and is used for mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP efficiently. However, “parasitic” energy transfer may be a more generalized mechanism in cancer biology than previously appreciated. Two recent papers in Science and Nature Medicine now show that lipolysis in host tissues also fuels tumor growth. These studies demonstrate that free fatty acids produced by host cell lipolysis are re-used via beta-oxidation (beta-OX) in cancer cell mitochondria. Thus, stromal catabolites (such as lactate, ketones, glutamine and free fatty acids) promote tumor growth by acting as high-energy onco-metabolites. As such, host catabolism, via autophagy, mitophagy and lipolysis, may explain the pathogenesis of cancer-associated cachexia and provides exciting new druggable targets for novel therapeutic interventions. Taken together, these findings also suggest that tumor cells promote their own growth and survival by behaving as a “parasitic organism.” Hence, we propose the term “Parasitic Cancer Metabolism” to describe this type of metabolic coupling in tumors. Targeting tumor cell mitochondria (OXPHOS and beta-OX) would effectively uncouple tumor cells from their hosts, leading to their acute starvation. In this context, we discuss new evidence that high-energy onco-metabolites (produced by the stroma) can confer drug resistance. Importantly, this metabolic chemo-resistance is reversed by blocking OXPHOS in cancer cell mitochondria with drugs like Metformin, a mitochondrial “poison.” In summary, parasitic cancer metabolism is achieved architecturally by dividing tumor tissue into at least two well-defined opposing “metabolic compartments:” catabolic and anabolic.

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

Mikhail V. Blagosklonny
Pages 4217 - 4224
http://dx.doi.org/10.4161/cc.10.24.18595
Abstract | PDF

Rapamycin prolongs healthy lifespan in yeast, flies and mammals and delays age-related diseases, including cancer and atherosclerosis. Rapamycin is considered for prevention of diabetic complications, such as retinopathy and nephropathy, and acute treatment with rapamycin decreases insulin resistance. However, under certain conditions, chronic administration of rapamycin may cause glucose intolerance and even provoke type II diabetes. This does not fit logically with its potential effects against diabetic complications. This also seems puzzling, because calorie restriction (CR) can prevent type II diabetes and its complications, and rapamycin mimics CR. It was somehow forgotten that almost two centuries ago, Claude Bernard discovered “starvation diabetes,” as shown later, characterized by glucose intolerance, decreased insulin, increased lipoproteins and ketones, gluconeogenesis and hepatic resistance to insulin. This reversible condition is not true diabetes: it does not lead to diabetic complications, and CR extends healthy lifespan. If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce “hunger diabetes.” But will rapamycin prevent true type II diabetes? Here are some answers.




REVIEW

p53 regulation: Teamwork between RING domains of Mdm2 and MdmX

Xinjiang Wang
Pages 4225 - 4229
http://dx.doi.org/10.4161/cc.10.24.18662
Abstract | PDF

p53 is a major tumor suppressor frequently inactivated through direct gene mutation and alternative mechanisms including overexpression of Mdm2 and MdmX. Both Mdm2 and MdmX are essential for negative regulation of p53 in vivo in a mutually dependent manner. The RING domain dependent E3 ligase activity of Mdm2 has been shown to be essential for negative regulation of p53. The prevailing model has dubbed MdmX as an inhibitor of p53 transcriptional activity through direct binding of its N-terminal domain to p53. However, recent findings established an essential role of the RING domain of MdmX in p53 degradation in vitro and in vivo. Biochemically, Mdm2 on its own is a monoubiquitinatuion E3 ligase, however, MdmX can convert Mdm2 into a polyubiquitination E3 ligase necessary for p53 proteasomal degradation in cells, through their RING-RING interactions. While Mdm2 is the catalytic components of Mdm2/MdmX E3 complex, MdmX is both the activating component and a substrate of the holoenzyme. Knock-in of RING mutant MdmX in mice causes p53-dependent embryonic lethality in a similar manner as knockout of MdmX whole gene. The new advance of the field assigned an essential role of the RING domain of MdmX in negative regulation of p53 in vivo, just like Mdm2 RING domain, through p53 degradation.




REPORTS

Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice

Vladimir N. Anisimov, Mark A. Zabezhinski, Irina G. Popovich, Tatiana S. Piskunova, Anna V. Semenchenko, Margarita L. Tyndyk, Maria N. Yurova, Svetlana V. Rosenfeld and Mikhail V. Blagosklonny
Pages 4230 - 4236
http://dx.doi.org/10.4161/cc.10.24.18486
Abstract | PDF

The nutrient-sensing TO R (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TO R, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an avenue to develop optimal doses and schedules of rapamycin as an anti-aging modality.

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

Krassimira Botcheva, Sean R. McCorkle, W.R. McCombie, John J. Dunn and Carl W. Anderson
Pages 4237 - 4249
http://dx.doi.org/10.4161/cc.10.24.18383
Abstract | PDF

We report here genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40% were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied, functional p53 binding sites and, to date, not observed by previous p53 genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands, in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely, the different chromatin landscape in normal, compared with cancer-derived cells, influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIPseq peaks to the recently published IMR90 methylome1 and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells.

Loss of stromal caveolin-1 expression in malignant melanoma metastases predicts poor survival

Karen N. Wu, Maria Queenan, Jonathan R. Brody, Magdalena Potoczek, Federica Sotgia, Michael P. Lisanti and Agnieszka K. Witkiewicz
Pages 4250 - 4255
http://dx.doi.org/10.4161/cc.10.24.18551
Abstract | PDF

Caveolins are the principal protein component of caveolae, plasma membrane invaginations found in most cell types. Caveolin-1 (Cav-1) plays a major role in oncogenesis through its various functions in lipid transport, membrane trafficking, and signal transduction. Increased expression of Cav-1 in tumor cells has been associated with aggressiveness and poor survival. More recently, loss of stromal Cav-1 expression was linked to poor survival and increased metastatic potential in breast and prostate cancer. To date, there is no study addressing the clinical significance of Cav-1 expression in malignant melanoma (MM). Our study consisted of 44 cases of MM: 12 MM lymph node metastases from patients with short survival, 12 MM lymph node metastases from patients with long survival and 20 primary MM. All cases were stained with Cav-1 antibodies. Cav-1 expression in melanoma and stromal cells was quantified using a 3 point scale: 0=no staining, 1=diffuse weak staining or strong staining in < 30% of cells, and 2 = diffuse strong staining. A score of 0-1 represented low Cav-1 expression and a score of 2 represented high Cav-1 expression. In patients with MM lymph node metastases, a low stromal Cav-1 expression was associated with shorter survival when compared to the high stromal Cav-1 expression group (median survival 252 days versus 3,508 days, p value 0.0054). Conversely, high Cav-1 expression in melanoma cells was associated with a longer survival in primary MM (p<0.0001). In conclusion, high expression of stromal Cav-1 correlates with longer survival in malignant melanoma metastases, and high expression of Cav-1 in melanoma cells correlates with longer survival in primary malignant melanoma.

miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions

Helge Siemens, Rene Jackstadt, Sabine Hünten, Markus Kaller, Antje Menssen, Ursula Götz and Heiko Hermeking
Pages 4256 - 4271
http://dx.doi.org/10.4161/cc.10.24.18552
Abstract | PDF

Recently, the inhibition of epithelial-mesenchymal-transition (EMT) by p53 has been described as a new mode of tumor suppression which presumably prevents metastasis. Here we report that activation of p53 down-regulates the EMT-inducing transcription factor SNAIL via induction of the miR-34a/b/c genes. Suppression of miR-34a/b/c caused up-regulation of SNAIL and cells displayed EMT markers and related features, as enhanced migration and invasion.  Ectopic miR-34a induced mesenchymal-epithelial-transition (MET) and down-regulation of SNAIL, which was mediated by a conserved miR-34a/b/c seed-matching sequence in the SNAIL 3’-UTR. miR-34a also down-regulated SLUG and ZEB1, as well as the stemness factors BMI1, CD44, CD133, OLFM4 and c-MYC. Conversely, the transcription factors SNAIL and ZEB1 bound to E-boxes in the miR-34a/b/c promoters, thereby repressing miR-34a and miR-34b/c expression. Since ectopic miR-34a prevented TGF-β-induced EMT, the repression of miR-34 genes by SNAIL and related factors is part of the EMT program. In conclusion, the frequent inactivation of p53 and/or miR-34a/b/c found in cancer may shift the equilibrium of these reciprocal regulations towards the mesenchymal state and thereby lock cells in a metastatic state.

Open Access Article

Conservation of all three p53 family members and Mdm2 and Mdm4 in the cartilaginous fish

David P. Lane, Arumugam Madhumalar, Alison P. Lee, Boon-Hui Tay, Chandra Verma, Sydney Brenner and Byrappa Venkatesh
Pages 4272 - 4279
http://dx.doi.org/10.4161/cc.10.24.18567
Abstract | PDF

Analysis of the genome of the elephant shark (Callorhinchus milii), a member of the cartilaginous fishes (Class Chondrichthyes), reveals that it encodes all three members of the p53 gene family, p53, p63 and p73, each with clear homology to the equivalent gene in bony vertebrates (Class Osteichthyes). Thus, the gene duplication events that lead to the presence of three family members in the vertebrates dates to before the Silurian era. It also encodes Mdm2 and Mdm4 genes but does not encode the p19^Arf gene. Detailed comparison of the amino acid sequences of these proteins in the vertebrates reveals that they are evolving at highly distinctive rates, and this variation occurs not only between the three family members but extends to distinct domains in each protein.

Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development

Andrea Weil, Karin Luce, Stefan Dröse, Ilka Wittig, Ulrich Brandt and Heinz D. Osiewacz
Pages 4280 - 4290
http://dx.doi.org/10.4161/cc.10.24.18560
Abstract | PDF

Different molecular pathways involved in maintaining mitochondrial function are of fundamental importance to control cellular homeostasis. Mitochondrial i-AAA protease is part of such a surveillance system and PaIAP is the putative ortholog in the fungal aging model Podospora anserina. Here we investigated the role of PaIAP in aging and development. Deletion of the gene encoding PaIAP resulted in a specific phenotype. When incubated at 27°C, spore germination and fruiting body formation are not different from that of the corresponding wild-type strain. Unexpectedly, the lifespan of the deletion strain is strongly increased. In contrast, cultivation at an elevated temperature of 37°C leads to impairments in spore germination and fruiting body formation, and to a reduced lifespan. The higher PaIAP abundance in wild-type strains of the fungus grown at elevated temperature and the phenotype of the deletion strain unmasks a temperaturerelated role of the protein. The protease appears to be part of a molecular system that has evolved to allow survival under changing temperatures as they characteristically occur in nature.

Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy

Soichiro Yoshida, Fumitaka Koga, Manabu Tatokoro, Satoru Kawakami, Yasuhisa Fujii, Jiro Kumagai, Len Neckers and Kazunori Kihara
Pages 4291 - 4299
http://dx.doi.org/10.4161/cc.10.24.18616
Abstract | PDF

Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-κB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC.

Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks

Adva Levy-Barda, Yaniv Lerenthal, Anthony J. Davis, Young Min Chung, Jeroen Essers, Zhengping Shao, Nicole van Vliet, David J. Chen, Mickey C-T. Hu, Roland Kanaar, Yael Ziv and Yosef Shiloh
Pages 4300 - 4310
http://dx.doi.org/10.4161/cc.10.24.18642
Abstract | PDF

The DNA damage response (DDR) is a complex signaling network that leads to damage repair while modulating numerous cellular processes. DNA double-strand breaks (DSBs)—a highly cytotoxic DNA lesion—activate this system most vigorously. The DSB response network is orchestrated by the ATM protein kinase, which phosphorylates key players in its various branches. Proteasome-mediated protein degradation plays an important role in the proteome dynamics following DNA damage induction. Here, we identify the nuclear proteasome activator PA28γ (REGγ; PSME3) as a novel DDR player. PA28γ depletion leads to cellular radiomimetic sensitivity and a marked delay in DSB repair. Specifically, PA28γ deficiency abrogates the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair. Furthermore, PA28γ is found to be an ATM target, being recruited to the DNA damage sites and required for rapid accumulation of proteasomes at these sites. Our data reveal a novel ATM-PA28γ-proteasome axis of the DDR that is required for timely coordination of DSB repair.

Oxygen sensing is impaired in ATM-defective cells

Maria Patrizia Mongiardi, Venturina Stagni, Manuela Natoli, Danilo Giaccari, Igea D’Agnano, Maria Laura Falchetti, Daniela Barilà and Andrea Levi
Pages 4311 - 4320
http://dx.doi.org/10.4161/cc.10.24.18663
Abstract | PDF

The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cell adaptation to decreasing oxygen levels. High oxygen tension promotes proteosomal degradation of HIF-1α via a pathway that requires hydroxylation of prolines 402 and 564. Low oxygen tension, hypoxia, inactivates the hydroxylases responsible for these modifications through a mechanism that is not fully understood but appears to require mitochondrial respiration and production of reactive oxygen species, ROS. Cells from individuals affected by ataxia telangiectasia syndrome have an impaired mitochondrial activity and a constitutive oxidative stress. Here we show that, in these cells, HIF-1α is efficiently degraded even in condition of low oxygen tension. Mechanistically this depends from a blunted increase in intracellular concentration of ROS in response to hypoxia which in turn is due to an increased cellular capacity of buffering ROS. We suggest that regulation of HIF-1α stability may depend on fold change of ROS relative to the basal level more than on their absolute value. Since elevated oxidative stress is a hallmark of many human disorders our finding may be relevant to different pathologies.

Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1

Sean Vance, Erqi Liu, Lili Zhao, Joshua D. Parsels, Leslie A. Parsels, Jeffery L. Brown, Jonathan Maybaum, Theodore S. Lawrence and Meredith A. Morgan
Pages 4321 - 4329
http://dx.doi.org/10.4161/cc.10.24.18661
Abstract | PDF

We have recently shown that inhibition of HRR (homologous recombination repair) by Chk1 (checkpoint kinase 1) inhibition radiosensitizes pancreatic cancer cells and others have demonstrated that Chk1 inhibition selectively sensitizes p53 mutant tumor cells. Furthermore, PARP1 [poly (ADP-ribose) polymerase-1] inhibitors dramatically radiosensitize cells with DNA double strand break repair defects. Thus, we hypothesized that inhibition of HRR (mediated by Chk1 via AZD7762) and PARP1 [via olaparib (AZD2281)] would selectively sensitize p53 mutant pancreatic cancer cells to radiation. We also used 2 isogenic p53 cell models to assess the role of p53 status in cancer cells and intestinal epithelial cells to assess overall cancer specificity. DNA damage response and repair were assessed by flow cytometry, γH2AX, and an HRR reporter assay. We found that the combination of AZD7762 and olaparib produced significant radiosensitization in p53 mutant pancreatic cancer cells and in all of the isogenic cancer cell lines. The magnitude of radiosensitization by AZD7762 and olaparib was greater in p53 mutant cells compared with p53 wild type cells. Importantly, normal intestinal epithelial cells were not radiosensitized. The combination of AZD7762 and olaparib caused G₂ checkpoint abrogation, inhibition of HRR, and persistent DNA damage responses. These findings demonstrate that the combination of Chk1 and PARP1 inhibition selectively radiosensitizes p53 mutant pancreatic cancer cells. Furthermore, these studies suggest that inhibition of HRR by Chk1 inhibitors may be a useful strategy for selectively inducing a BRCA1/2 ‘deficient-like’ phenotype in p53 mutant tumor cells, while sparing normal tissue.

Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop

Fabio Valenti, Francesca Fausti, Francesca Biagioni, Tal Shay, Giulia Fontemaggi, Eytan Domany, Michael B. Yaffe, Sabrina Strano, Giovanni Blandino and Silvia Di Agostino
Pages 4330 - 4340
http://dx.doi.org/10.4161/cc.10.24.18682
Abstract | PDF

Aberrant activation of kinases has emerged to be a key event along with tumor progression, maintenance of tumor phenotype and response to anticancer treatments. This study documents the existence of an oncogenic auto-regulatory feedback loop that includes the Polo-like kinase-2 (Snk/Plk2) and mutant p53 proteins. Plk2 protein binds to and phosphorylates mutant p53, thereby potentiating its oncogenic activities. Phosphorylated mutant p53 binds more efficiently to p300 consequently strengthening its own transcriptional activity. Plk2 gene is regulated at a transcriptional level by both wt- and mutant p53 proteins. This leads to growth suppression or enhanced cell proliferation and chemo-resistance, respectively. In turn, the siRNA-mediated knock down of either mutant p53 or Plk2 proteins significantly curtails the growth properties of tumor cells and their chemo-resistance to anticancer treatments. Therefore, this paper identifies a novel tumor network including Plk2 and mutant p53 proteins whose triggering in response to DNA damage might disclose important implications for the treatment of human cancers.




LETTER TO THE EDITOR

Thiostrepton, proteasome inhibitors and FOXM1

Andrei L. Gartel
Pages 4341 - 4342
http://dx.doi.org/10.4161/cc.10.24.18544
PDF