Abstract
Tumor recurrence after chemotherapy or radiation remains a major obstacle to successful cancer treatment. A subset of cancer cells, termed cancer stem cells, can elude conventional treatments and eventually regenerate a tumor that is more aggressive. Despite the large number of studies, molecular events that govern the emergence of aggressive therapy-resistant cells with stem cell properties after chemotherapy are poorly defined. The present study provides evidence for the rare escape of tumor cells from drug-induced cell death, after an intermediate stay in a non-cycling senescent stage followed by unstable multiplication characterized by spontaneous cell death. However, some cells appear to escape and generate stable colonies with an aggressive tumor stem cell-like phenotype. These cells displayed higher CD133 and Oct-4 expression. Notably, the drug-selected cells that contained low levels of reactive oxygen species (ROS) also showed an increase in antioxidant enzymes. Consistent with this in vitro experimental data, we observed lower levels of ROS in breast tumors obtained after neoadjuvant chemotherapy compared with samples that did not receive preoperative chemotherapy. These latter tissues also expressed enhanced levels of ROS defenses with enhanced expression of superoxide dismutase. Higher levels of Oct-4 and CD133 were also observed in tumors obtained after neoadjuvant chemotherapy. Further studies provided evidence for the stabilization of Nrf2 due to reduced 26 S proteasome activity and increased p21 association as the driving signaling event that contributes to the transition from a high ROS quiescent state to a low ROS proliferating stage in drug-induced tumor stem cell enrichment.
http://m.jbc.org/content/286/43/37813.short
Drug-induced Senescence Generates Chemoresistant Stemlike Cells with Low Reactive Oxygen Species*
Drug-induced Senescence Generates Chemoresistant Stemlike Cells with Low Reactive Oxygen Species*
Last edited by D.ap on Sun Feb 25, 2018 6:07 am, edited 3 times in total.
Debbie
Exploring the Histogenesis and Diagnostic Strategy Using Immunoassay and RT-PCR in Alveolar Soft Part Sarcoma
Exploring the Histogenesis and Diagnostic Strategy Using Immunoassay and RT-PCR in Alveolar Soft Part Sarcoma
Abstract
Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, but it’s easily misdiagnosed in rare locations. The derivation of ASPS is still uncertain, therefore we conducted this study to explore the histogenesis of ASPS by analyzing stem cell markers (ALDH1, CD29, CD133 and Nestin). Protein TFE3 and fusion gene ASPS-TFE3 were tested in paraffin to explore diagnostic strategy and molecular pathological features. In this study, nine cases of ASPS were immunostained with stiem cell surface markers (ALDH1, CD29, CD133 and Nestin) and protein TFE3. Seven cases of ASPS mRNA were successfully extracted from nine paraffin-embedded tissues. The expression of fusion gene ASPL-TFE3 was examined by reverse transcriptase-polymerase chain reaction. The immunohistochemical staining of nine patients showed that CD29 and Nestin were negative in all nine cases (0/9). CD133 was weakly positive in one cases (1/9) and ALDH1 was weakly positive in one cases (1/9). TFE3 was positive in nine cases (9/9). Seven paraffin tissues could be successfully extracted with mRNA in nine cases. The results of Reverse Transcription Polymerase Chain Reaction (RT-PCR) showed that ASPL-TFE3 fusion transcripts could be tested in the seven cases (four cases being type 2 and three cases being type 1). The positive rate of CD133 and ALDH1 were less than 1% and the expression of CD29 and Nestin were negative in ASPS. Immunohistochemistry results indicated that the histogenesis of ASPS maybe not derive from mesenchymal stem cells. Immunohistochemistry staining showed that TFE3 protein expression was highly sensitive in ASPS. Furthermore, RT-PCR results showed that fusion gene ASPL-TFE3 (ASPL-TFE3 type 1 and ASPL-TFE3 type 2) was expressed in ASPS, which could provide information for clinical molecular pathological diagnosis and improve the diagnosis rate of rare atypical ASPS.
https://www.springermedizin.de/explorin ... a/13341784
Abstract
Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, but it’s easily misdiagnosed in rare locations. The derivation of ASPS is still uncertain, therefore we conducted this study to explore the histogenesis of ASPS by analyzing stem cell markers (ALDH1, CD29, CD133 and Nestin). Protein TFE3 and fusion gene ASPS-TFE3 were tested in paraffin to explore diagnostic strategy and molecular pathological features. In this study, nine cases of ASPS were immunostained with stiem cell surface markers (ALDH1, CD29, CD133 and Nestin) and protein TFE3. Seven cases of ASPS mRNA were successfully extracted from nine paraffin-embedded tissues. The expression of fusion gene ASPL-TFE3 was examined by reverse transcriptase-polymerase chain reaction. The immunohistochemical staining of nine patients showed that CD29 and Nestin were negative in all nine cases (0/9). CD133 was weakly positive in one cases (1/9) and ALDH1 was weakly positive in one cases (1/9). TFE3 was positive in nine cases (9/9). Seven paraffin tissues could be successfully extracted with mRNA in nine cases. The results of Reverse Transcription Polymerase Chain Reaction (RT-PCR) showed that ASPL-TFE3 fusion transcripts could be tested in the seven cases (four cases being type 2 and three cases being type 1). The positive rate of CD133 and ALDH1 were less than 1% and the expression of CD29 and Nestin were negative in ASPS. Immunohistochemistry results indicated that the histogenesis of ASPS maybe not derive from mesenchymal stem cells. Immunohistochemistry staining showed that TFE3 protein expression was highly sensitive in ASPS. Furthermore, RT-PCR results showed that fusion gene ASPL-TFE3 (ASPL-TFE3 type 1 and ASPL-TFE3 type 2) was expressed in ASPS, which could provide information for clinical molecular pathological diagnosis and improve the diagnosis rate of rare atypical ASPS.
https://www.springermedizin.de/explorin ... a/13341784
Debbie
Re: Drug-induced Senescence Generates Chemoresistant Stemlike Cells with Low Reactive Oxygen Species*
In keeping with the topic of chemo resistant ASPS,
The role of p53 in cancer drug resistance and targeted chemotherapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352454/
The role of p53 in cancer drug resistance and targeted chemotherapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352454/
Debbie
The role of p53 in cancer drug resistance and targeted chemotherapy
The role of p53 in cancer drug resistance and targeted chemotherapy
Abstract
Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.
Keywords: cytotoxic chemotherapy, drug resistance, medicinal chemistry, prognostic factors, targeted chemotherapy
Abstract
Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.
Keywords: cytotoxic chemotherapy, drug resistance, medicinal chemistry, prognostic factors, targeted chemotherapy
Debbie
Re: Drug-induced Senescence Generates Chemoresistant Stemlike Cells with Low Reactive Oxygen Species*
INTRODUCTION
p53 unfurled
TP53 (tumor suppressor gene p53) is one of the most well-studied tumor suppressor genes. Because of its pivotal role in protecting from malignancies, p53 is called “guardian of the genome” [1–4]. Its signaling is triggered through myriad cellular events ranging from DNA damage to hypoxia, stress and a plethora of other causes [2, 3, 5–7]. Upon activation, p53 acts as zinc-containing transcription factor [7–11] and regulates downstream genes that are involved in DNA repair, cell cycle arrest or apoptosis [6, 7, 12–15]. Apoptosis is initiated by trans-activating pro-apoptotic proteins such as PUMA (p53 upregulated modulator of apoptosis) [15, 16], FAS (cell surface death receptor) [2, 15], or BAX (Bcl-2-associated X protein) [2, 6, 7, 15–17]. In contrast, cell cycle arrest is induced by p53 via trans-activating genes such as p21 (CDK-inhibitor 1, cyclin dependent kinase) [2, 6, 7, 15] and others [3, 15]. Interestingly, p53 itself is capable of triggering cellular responses (survival or induced cell death) as well. This ability may vary according to the cell type, intensity of stress signal and/or extent of cellular damage [15]. Besides an augmentation of the protein level, the activation of p53 also includes post-translational modifications in the protein itself, which subsequently activates p53-targeted genes [18]. One such post-translational modification is induced by DNA damage. Similar damage leads to activation of kinases like ATM (Ataxia telangiectasia-mutated protein) [3, 4, 17, 18] and Chk2 (Checkpoint kinase 2), which subsequently phosphorylate p53, resulting in p53-dependent cell cycle arrest or apoptosis [18]. In normal cells, expression of p53 is low [7, 13] and its half-life is about 20 min [13]. However, in the case of cellular stress, p53's half-life is extended to several hours, which consequentially results in elevated p53 protein levels in the cell [18]. As cellular gatekeeper [7, 12, 18, 19], a primary role of p53 is to recognize, whether damage is irrevocable and accordingly induce apoptosis [18, 19].
p53 unfurled
TP53 (tumor suppressor gene p53) is one of the most well-studied tumor suppressor genes. Because of its pivotal role in protecting from malignancies, p53 is called “guardian of the genome” [1–4]. Its signaling is triggered through myriad cellular events ranging from DNA damage to hypoxia, stress and a plethora of other causes [2, 3, 5–7]. Upon activation, p53 acts as zinc-containing transcription factor [7–11] and regulates downstream genes that are involved in DNA repair, cell cycle arrest or apoptosis [6, 7, 12–15]. Apoptosis is initiated by trans-activating pro-apoptotic proteins such as PUMA (p53 upregulated modulator of apoptosis) [15, 16], FAS (cell surface death receptor) [2, 15], or BAX (Bcl-2-associated X protein) [2, 6, 7, 15–17]. In contrast, cell cycle arrest is induced by p53 via trans-activating genes such as p21 (CDK-inhibitor 1, cyclin dependent kinase) [2, 6, 7, 15] and others [3, 15]. Interestingly, p53 itself is capable of triggering cellular responses (survival or induced cell death) as well. This ability may vary according to the cell type, intensity of stress signal and/or extent of cellular damage [15]. Besides an augmentation of the protein level, the activation of p53 also includes post-translational modifications in the protein itself, which subsequently activates p53-targeted genes [18]. One such post-translational modification is induced by DNA damage. Similar damage leads to activation of kinases like ATM (Ataxia telangiectasia-mutated protein) [3, 4, 17, 18] and Chk2 (Checkpoint kinase 2), which subsequently phosphorylate p53, resulting in p53-dependent cell cycle arrest or apoptosis [18]. In normal cells, expression of p53 is low [7, 13] and its half-life is about 20 min [13]. However, in the case of cellular stress, p53's half-life is extended to several hours, which consequentially results in elevated p53 protein levels in the cell [18]. As cellular gatekeeper [7, 12, 18, 19], a primary role of p53 is to recognize, whether damage is irrevocable and accordingly induce apoptosis [18, 19].
Debbie
Re: Drug-induced Senescence Generates Chemoresistant Stemlike Cells with Low Reactive Oxygen Species*
Should actually be from “The role of p53 in cancer drug resistance and targeted chemotherapy”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352454/D.ap wrote: ↑Fri Mar 02, 2018 5:56 am INTRODUCTION
p53 unfurled
TP53 (tumor suppressor gene p53) is one of the most well-studied tumor suppressor genes. Because of its pivotal role in protecting from malignancies, p53 is called “guardian of the genome” [1–4]. Its signaling is triggered through myriad cellular events ranging from DNA damage to hypoxia, stress and a plethora of other causes [2, 3, 5–7]. Upon activation, p53 acts as zinc-containing transcription factor [7–11] and regulates downstream genes that are involved in DNA repair, cell cycle arrest or apoptosis [6, 7, 12–15]. Apoptosis is initiated by trans-activating pro-apoptotic proteins such as PUMA (p53 upregulated modulator of apoptosis) [15, 16], FAS (cell surface death receptor) [2, 15], or BAX (Bcl-2-associated X protein) [2, 6, 7, 15–17]. In contrast, cell cycle arrest is induced by p53 via trans-activating genes such as p21 (CDK-inhibitor 1, cyclin dependent kinase) [2, 6, 7, 15] and others [3, 15]. Interestingly, p53 itself is capable of triggering cellular responses (survival or induced cell death) as well. This ability may vary according to the cell type, intensity of stress signal and/or extent of cellular damage [15]. Besides an augmentation of the protein level, the activation of p53 also includes post-translational modifications in the protein itself, which subsequently activates p53-targeted genes [18]. One such post-translational modification is induced by DNA damage. Similar damage leads to activation of kinases like ATM (Ataxia telangiectasia-mutated protein) [3, 4, 17, 18] and Chk2 (Checkpoint kinase 2), which subsequently phosphorylate p53, resulting in p53-dependent cell cycle arrest or apoptosis [18]. In normal cells, expression of p53 is low [7, 13] and its half-life is about 20 min [13]. However, in the case of cellular stress, p53's half-life is extended to several hours, which consequentially results in elevated p53 protein levels in the cell [18]. As cellular gatekeeper [7, 12, 18, 19], a primary role of p53 is to recognize, whether damage is irrevocable and accordingly induce apoptosis [18, 19].
Debbie