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RB1 Status in Triple Negative Breast Cancer Cells Dictates Response to Radiation Treatment and Selective Therapeutic Drugs  [PDF]
Tyler J. W. Robinson, Jeff C. Liu, Frederick Vizeacoumar, Thomas Sun, Neil Maclean, Sean E. Egan, Aaron D. Schimmer, Alessandro Datti, Eldad Zacksenhaus
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078641
Abstract: Triple negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which only chemotherapy and radiation therapy are currently available. The retinoblastoma (RB1) tumor suppressor is frequently lost in human TNBC. Knockdown of RB1 in luminal BC cells was shown to affect response to endocrine, radiation and several antineoplastic drugs. However, the effect of RB1 status on radiation and chemo-sensitivity in TNBC cells and whether RB1 status affects response to divergent or specific treatment are unknown. Using multiple basal-like and claudin-low cell lines, we hereby demonstrate that RB-negative TNBC cell lines are highly sensitive to gamma-irradiation, and moderately more sensitive to doxorubicin and methotrexate compared to RB-positive TNBC cell lines. In contrast, RB1 status did not affect sensitivity of TNBC cells to multiple other drugs including cisplatin (CDDP), 5-fluorouracil, idarubicin, epirubicin, PRIMA-1met, fludarabine and PD-0332991, some of which are used to treat TNBC patients. Moreover, a non-biased screen of ~3400 compounds, including FDA-approved drugs, revealed similar sensitivity of RB-proficient and -deficient TNBC cells. Finally, ESA+/CD24?/low/CD44+ cancer stem cells from RB-negative TNBC lines were consistently more sensitive to gamma-irradiation than RB-positive lines, whereas the effect of chemotherapy on the cancer stem cell fraction varied irrespective of RB1 expression. Our results suggest that patients carrying RB-deficient TNBCs would benefit from gamma-irradiation as well as doxorubicin and methotrexate therapy, but not necessarily from many other anti-neoplastic drugs.
Sestrin2 Modulates AMPK Subunit Expression and Its Response to Ionizing Radiation in Breast Cancer Cells  [PDF]
Toran Sanli, Katja Linher-Melville, Theodoros Tsakiridis, Gurmit Singh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032035
Abstract: Background The sestrin family of stress-responsive genes (SESN1-3) are suggested to be involved in regulation of metabolism and aging through modulation of the AMPK-mTOR pathway. AMP-activated protein kinase (AMPK) is an effector of the tumour suppressor LKB1, which regulates energy homeostasis, cell polarity, and the cell cycle. SESN1/2 can interact directly with AMPK in response to stress to maintain genomic integrity and suppress tumorigenesis. Ionizing radiation (IR), a widely used cancer therapy, is known to increase sestrin expression, and acutely activate AMPK. However, the regulation of AMPK expression by sestrins in response to IR has not been studied in depth. Methods and Findings Through immunoprecipitation we observed that SESN2 directly interacted with the AMPKα1β1γ1 trimer and its upstream regulator LKB1 in MCF7 breast cancer cells. SESN2 overexpression was achieved using a Flag-tagged SESN2 expression vector or a stably-integrated tetracycline-inducible system, which also increased AMPKα1 and AMPKβ1 subunit phosphorylation, and co-localized with phosphorylated AMPKα-Thr127 in the cytoplasm. Furthermore, enhanced SESN2 expression increased protein levels of LKB1 and AMPKα1β1γ1, as well as mRNA levels of LKB1, AMPKα1, and AMPKβ1. Treatment of MCF7 cells with IR elevated AMPK expression and activity, but this effect was attenuated in the presence of SESN2 siRNA. In addition, elevated SESN2 inhibited IR-induced mTOR signalling and sensitized MCF7 cells to IR through an AMPK-dependent mechanism. Conclusions Our results suggest that in breast cancer cells SESN2 is associated with AMPK, it is involved in regulation of basal and IR-induced expression and activation of this enzyme, and it mediates sensitization of cancer cells to IR.
Comprehensive data-driven analysis of the impact of chemoinformatic structure on the genome-wide biological response profiles of cancer cells to 1159 drugs  [PDF]
Suleiman A. Khan,Ali Faisal,John Patric Mpindi,Juuso A. Parkkinen,Tuomo Kalliokoski,Antti Poso,Olli P. Kallioniemi,Krister Wennerberg,Samuel Kaski
Quantitative Biology , 2011,
Abstract: Detailed and systematic understanding of the biological effects of millions of available compounds on living cells is a significant challenge. As most compounds impact multiple targets and pathways, traditional methods for analyzing structure-function relationships are not comprehensive enough. Therefore more advanced integrative models are needed for predicting biological effects elicited by specific chemical features. As a step towards creating such computational links we developed a data-driven chemical systems biology approach to comprehensively study the relationship of 76 structural 3D-descriptors (VolSurf, chemical space) of 1159 drugs with the gene expression responses (biological space) they elicited in three cancer cell lines. The analysis covering 11350 genes was based on data from the Connectivity Map. We decomposed these biological response profiles into components, each linked to a characteristic chemical descriptor profile. The integrated quantitative analysis of the chemical and biological spaces was more informative about protein-target based drug similarity than either dataset separately. We identified ten major components that link distinct VolSurf features across multiple compounds to specific biological activity types. For example, component 2 (hydrophobic properties) strongly links to DNA damage response, while component 3 (hydrogen bonding) connects to metabolic stress. Individual structural and biological features were often linked to one cell line only, such as leukemia cells (HL-60) specifically responding to cardiac glycosides. In summary, our approach identified specific chemical structures shared across multiple drugs causing distinct biological responses. The decoding of such systematic chemical-biological relationships is necessary to build better models of drug effects, including unidentified types of molecular properties with strong biological effects.
Mechanisms of Radiation Toxicity in Transformed and Non-Transformed Cells  [PDF]
Ronald-Allan M. Panganiban,Andrew L. Snow,Regina M. Day
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140815931
Abstract: Radiation damage to biological systems is determined by the type of radiation, the total dosage of exposure, the dose rate, and the region of the body exposed. Three modes of cell death—necrosis, apoptosis, and autophagy—as well as accelerated senescence have been demonstrated to occur in vitro and in vivo in response to radiation in cancer cells as well as in normal cells. The basis for cellular selection for each mode depends on various factors including the specific cell type involved, the dose of radiation absorbed by the cell, and whether it is proliferating and/or transformed. Here we review the signaling mechanisms activated by radiation for the induction of toxicity in transformed and normal cells. Understanding the molecular mechanisms of radiation toxicity is critical for the development of radiation countermeasures as well as for the improvement of clinical radiation in cancer treatment.
Epigenetics Meets Radiation Biology as a New Approach in Cancer Treatment  [PDF]
Joong-Gook Kim,Moon-Taek Park,Kyu Heo,Kwang-Mo Yang,Joo Mi Yi
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140715059
Abstract: Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer.
Comprehensive data-driven analysis of the impact of chemoinformatic structure on the genome-wide biological response profiles of cancer cells to 1159 drugs
Suleiman A Khan, Ali Faisal, John P Mpindi, Juuso A Parkkinen, Tuomo Kalliokoski, Antti Poso, Olli P Kallioniemi, Krister Wennerberg, Samuel Kaski
BMC Bioinformatics , 2012, DOI: 10.1186/1471-2105-13-112
Abstract: Integrated analysis of both the chemical and biological space was more informative than either dataset alone in predicting drug similarity as measured by shared protein targets. We identified ten major components that link distinct VolSurf chemical features across multiple compounds to specific cellular responses. For example, component 2 (hydrophobic properties) strongly linked to DNA damage response, while component 3 (hydrogen bonding) was associated with metabolic stress. Individual structural and biological features were often linked to one cell line only, such as leukemia cells (HL-60) specifically responding to cardiac glycosides.In summary, our approach identified several novel links between specific chemical structure properties and distinct biological responses in cells incubated with these drugs. Importantly, the analysis focused on chemical-biological properties that emerge across multiple drugs. The decoding of such systematic relationships is necessary to build better models of drug effects, including unanticipated types of molecular properties having strong biological effects.
Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms  [PDF]
Hossein Mozdarani
Genes , 2012, DOI: 10.3390/genes3010090
Abstract: Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity). It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation therapy, all these phenomena should be taken into account.
Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells
Bisrat G Debeb, Xiaomei Zhang, Savitri Krishnamurthy, Hui Gao, Evan Cohen, Li Li, Angel A Rodriguez, Melissa D Landis, Anthony Lucci, Naoto T Ueno, Fredika Robertson, Wei Xu, Lara Lacerda, Thomas A Buchholz, Massimo Cristofanilli, James M Reuben, Michael T Lewis, Wendy A Woodward
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-180
Abstract: 293T cells can be readily cultured and passaged as spheres in serum-free stem cell promoting culture conditions. Cells cultured in vitro as three-dimensional spheres (3D) were shown to contain higher ALDH1 and CD44+/CD24- population compared to monolayer cells. These cells were also resistant to radiation and upregulate stem cell survival signaling including β-catenin, Notch1 and Survivin in response to radiation. Moreover, 3D spheres generated from the 293T cells have increased expression of mesenchymal genes including vimentin, n-cadherin, zeb1, snail and slug as well as pro-metastatic genes RhoC, Tenascin C and MTA1. In addition, microRNAs implicated in self-renewal and metastases were markedly reduced in 3D spheres.293T cells exhibit a cancer stem cell-like phenotype when cultured as 3D spheres and represent an important research tool for studying the molecular and biological mechanisms of cancer stem cells and for testing and developing novel targets for cancer therapy.The cancer stem cell theory proposes that a subpopulation of cells, the cancer stem cells, exist in solid tumors as well as cancers of hematopoietic origin and constitute a reservoir of self-sustaining cells with the exclusive ability to self-renew and maintain the tumor. These cancer stem cells have the capacity to both divide and expand the cancer stem cell pool and to differentiate into the heterogeneous non-tumorigenic cancer cell types that constitute the bulk of the cancer cells within the tumor [1]. Cancer stem cells have been proposed to play a role in tumorigenesis and metastasis [2-4] as well as in resistance to radiation and chemotherapy [5-9]. Thus, it may be necessary to target and eliminate these cells to eradicate cancers.Cancer stem cells have been identified in a mounting number of human malignancies. Using approaches developed in the hematopoietic malignancies, Clarke and colleagues demonstrated the existence of a subpopulation of tumorigenic cells (or tumor-initiating cells), i
Heritability of Radiation Response in Lung Cancer Families  [PDF]
Albert Rosenberger,Ute R?ssler,Sabine Hornhardt,Wiebke Sauter,Heike Bickeb?ller,H.-Erich Wichmann,Maria Gomolka
Genes , 2012, DOI: 10.3390/genes3020248
Abstract: Radiation sensitivity is assumed to be a cancer susceptibility factor due to impaired DNA damage signalling and repair. Relevant genetic factors may also determine the observed familial aggregation of early onset lung cancer. We investigated the heritability of radiation sensitivity in families of 177 Caucasian cases of early onset lung cancer. In total 798 individuals were characterized for their radiation-induced DNA damage response. DNA damage analysis was performed by alkaline comet assay before and after in vitro irradiation of isolated lymphocytes. The cells were exposed to a dose of 4 Gy and allowed to repair induced DNA-damage up to 60 minutes. The primary outcome parameter Olive Tail Moment was the basis for heritability estimates. Heritability was highest for basal damage (without irradiation) 70% (95%-CI: 51%–88%) and initial damage (directly after irradiation) 65% (95%-CI: 47%–83%) and decreased to 20%–48% for the residual damage after different repair times. Hence our study supports the hypothesis that genomic instability represented by the basal DNA damage as well as radiation induced and repaired damage is highly heritable. Genes influencing genome instability and DNA repair are therefore of major interest for the etiology of lung cancer in the young. The comet assay represents a proper tool to investigate heritability of the radiation sensitive phenotype. Our results are in good agreement with other mutagen sensitivity assays.
Mechanisms of chemoresistance in cancer stem cells
Lissa Nurrul Abdullah, Edward Kai-Hua Chow
Clinical and Translational Medicine , 2013, DOI: 10.1186/2001-1326-2-3
Abstract: Our understanding of cancer has changed over the years, owing to rapid advances in oncology research. The disease itself is not only characterized as a mass of excessive, uncontrolled growth of abnormal cells but is also defined by the dynamic alterations in the genome that cause cancer [1]. Left unchecked, cancer progression leads to disruption of normal biological processes via cellular invasion into local adjacent tissues and distal organs through metastasis. In addition to conventional cancer treatments such as surgery, radiation and cytotoxic chemotherapy, more selective treatments based on increased understanding of tumor biology and specific tumor subtypes have also become available [2]. Even with these advances in cancer therapy, chemotherapy remains an important component of cancer treatment. Currently, the complete elimination of cancer continues to elude oncologists as 90% of drug failures in metastatic cancers are attributed to chemoresistance [3]. Understanding the mechanisms by which chemoresistance can occur is important to developing novel therapeutic approaches to treating cancer.In some cases, intrinsic chemoresistance may result in the survival of a population of tumor cells that subsequently leads to recurrence following treatment. This may be particularly true for tumors that are composed of a heterogeneous population of cells. For heterogenous tumors, the tumor initiating potential and drug sensitivity of different tumor cells within the same tumor bulk has yielded two models of cancer initiation: the stochastic model and the hierarchical model [4]. The stochastic model proposes that there is no variation in tumor initiating potential among different tumor subpopulations and that tumor cell growth is dependent on immune response, microenvironment and intrinsic gene regulatory signals. In contrast, the hierarchical concept suggests that different subpopulations of cells within a tumor have varying levels or absence of tumor initiating potential.
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