Search

Recent work in several model organisms has revealed that apoptotic cells are able to stimulate neighboring surviving cells to undergo additional proliferation, a phenomenon termed apoptosis-induced proliferation. This process depends critically on apoptotic caspases such as Dronc, the Caspase-9 ortholog in Drosophila, and may have important implications for tumorigenesis. While it is known that Dronc can induce the activity of Jun N-terminal kinase (JNK) for apoptosis-induced proliferation, the mechanistic details of this activation are largely unknown. It is also controversial if JNK activity occurs in dying or in surviving cells. Signaling molecules of the Wnt and BMP families have been implicated in apoptosis-induced proliferation, but it is unclear if they are the only ones. To address these questions, we have developed an efficient assay for screening and identification of genes that regulate or mediate apoptosis-induced proliferation. We have identified a subset of genes acting upstream of JNK activity including Rho1. We also demonstrate that JNK activation occurs both in apoptotic cells as well as in neighboring surviving cells. In a genetic screen, we identified signaling by the EGFR pathway as important for apoptosis-induced proliferation acting downstream of JNK signaling. These data underscore the importance of genetic screening and promise an improved understanding of the mechanisms of apoptosis-induced proliferation. [ABSTRACT FROM AUTHOR]

Recent work in several model organisms has revealed that apoptotic cells are able to stimulate neighboring surviving cells to undergo additional proliferation, a phenomenon termed apoptosis-induced proliferation. This process depends critically on apoptotic caspases such as Dronc, the Caspase-9 ortholog in Drosophila, and may have important implications for tumorigenesis. While it is known that Dronc can induce the activity of Jun N-terminal kinase (JNK) for apoptosis-induced proliferation, the mechanistic details of this activation are largely unknown. It is also controversial if JNK activity occurs in dying or in surviving cells. Signaling molecules of the Wnt and BMP families have been implicated in apoptosis-induced proliferation, but it is unclear if they are the only ones. To address these questions, we have developed an efficient assay for screening and identification of genes that regulate or mediate apoptosis-induced proliferation. We have identified a subset of genes acting upstream of JNK activity including Rho1. We also demonstrate that JNK activation occurs both in apoptotic cells as well as in neighboring surviving cells. In a genetic screen, we identified signaling by the EGFR pathway as important for apoptosis-induced proliferation acting downstream of JNK signaling. These data underscore the importance of genetic screening and promise an improved understanding of the mechanisms of apoptosis-induced proliferation. [ABSTRACT FROM AUTHOR]

Background: Cancer is a life-threatening condition with an economic burden on societies. Phytotherapy is rapidly taking place in cancer research to increase the success of treatment and quality of life. Thymoquinone (TQ) is the main active phenolic compound obtained from the essential oil of the Nigella sativa (black cumin) plant seed. For a long time, black cumin has been used traditionally for the remedy of different diseases because of its various biological effects. It has been shown that most of these effects of black cumin seeds are due to TQ. TQ became a popular research topic for phytotherapy studies for its potential therapeutic applications, and more research is going on to fully understand its mechanisms of action, safety, and efficacy in humans. KRAS is a gene that regulates cell division and growth. Monoallelic variants in KRAS result in uncontrollable cell division, leading to cancer development. Studies have shown that cancer cells with KRAS mutations are often resistant to certain types of chemotherapy and targeted therapies., Objective: This study aimed to compare the effect of TQ on cancer cells with and without KRAS mutation to better understand the reason why TQ may have different anticancer effects in the different types of cancer cells., Methods: TQ was investigated for its cytotoxic and apoptotic effects in laryngeal cancer cells (HEp-2) without KRAS mutation and compared to mutant KRAS -transfected larynx cancer cells and KRAS mutation-carrying lung cancer cells (A549)., Results: We showed that TQ has more cytotoxic and apoptotic effects on laryngeal cancer cells without KRAS mutation than in cells with mutation., Conclusion: KRAS mutations decrease the effect of TQ on cell viability and apoptosis, and further studies are needed to fully understand the relationship between KRAS mutations and thymoquinone effectiveness in cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions - (CTG) DM1 in DMPK and (CCTG) DM2 in CNBP Although transcription of mutant repeats into (CUG) DM1 or (CCUG) DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG) DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG) n repeats of variable length ( n =16 and 106). Expression of noncoding (CCUG) 106 , but not (CCUG) 16 , in muscle and retinal cells led to the formation of ribonuclear foci and mis-splicing of genes implicated in DM pathology. Mis-splicing could be rescued by co-expression of human MBNL1, but not by CUGBP1 (CELF1) complementation. Flies with (CCUG) 106 displayed strong disruption of external eye morphology and of the underlying retina. Furthermore, expression of (CCUG) 106 in developing retinae caused a strong apoptotic response. Inhibition of apoptosis rescued the retinal disruption in (CCUG) 106 flies. Finally, we tested two chemical compounds that have shown therapeutic potential in DM1 models. Whereas treatment of (CCUG) 106 flies with pentamidine had no effect, treatment with a PKR inhibitor blocked both the formation of RNA foci and apoptosis in retinae of (CCUG) 106 flies. Our data indicate that expression of expanded (CCUG) DM2 repeats is toxic, causing inappropriate cell death in affected fly eyes. Our Drosophila DM2 model might provide a convenient tool for in vivo drug screening., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

The cancer stem cell hypothesis emphasizes that cancers are driven by cells having stem cell properties, and it is believed that cancer stem cells (CSCs) may be responsible for resistance against therapeutic approaches and for recurrent tumors. Since the biology of the normal breast requires large numbers of stem cells, it has been thought that breast stem cells play an important role in initiating breast cancer. A better characterization of breast CSCs appears to be an essential step to improve the understanding of the biology of breast cancer and its management. The scope of this study was to isolate breast CSCs from a breast cancer cell line (MCF-7) using cell surface markers, and to test whether these cells have any resistance to autophagic cell death mechanisms mediated by commonly used chemotherapies and hormonal therapies such as doxorubicin (adriamycin) and tamoxifen (anti-estrogen), respectively. For this purpose, the CD44+/CD24-/low MCF-7 breast cancer stem/progenitor cell population was isolated and treated with doxorubicin or tamoxifen and evaluated for their response to growth, autophagy and apoptosis. Our findings suggest that CD44+/CD24-/low cells were less sensitive to doxorubicin, but did not demonstrate a significant difference towards tamoxifen in regards to the induction of autophagy.