AMP-Activated Protein Kinase:Friend or Foe in Cancer

The AMP-activated protein kinase (AMPK) is activated by energy stress and restores homeostasis by switching on catabolism, while switching off cell growth and proliferation. Findings that AMPK acts downstream of the tumor suppressor LKB1 have suggested that AMPK might also suppress tu-morigenesis. In mouse models of B and T cell lymphoma in which genetic loss of AMPK occurred before tumor initiation, tumorigenesis was accelerated , confirming that AMPK has tumor-suppressor functions. However, when loss of AMPK in a T cell lymphoma model occurred after tumor initiation , or simultaneously with tumor initiation in a lung cancer model, the disease was ameliorated. Thus, once tumorigenesis has occurred, AMPK switches from tumor suppression to tumor promotion. Analysis of alterations in AMPK genes in human cancers suggests similar dichotomies, with some genes being frequently amplified while others are mutated. Overall, while AMPK-activating drugs might be effective in preventing cancer, in some cases AMPK inhibitors might be required to treat it

Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma

Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells. In\ud this study, we examined whether the PPARc-activated pathway contributed to the antitumor effect of two cannabinoids,\ud D9-tetrahydrocannabinol (THC) and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity\ud and intracellular level of PPARc mRNA and protein, which was abolished by the PPARc inhibitor GW9662. Moreover, genetic\ud ablation with small interfering RNA (siRNA), as well as pharmacological inhibition of PPARc decreased the cannabinoid-induced\ud cell death and apoptosis. Likewise, GW9662 totally blocked the antitumoral action of cannabinoids in xenograft-induced HCC\ud tumors in mice. In addition, PPARc knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62,\ud suggesting that PPARc is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the\ud endoplasmic reticulum stress-related protein tribbles homolog 3 (TRIB3) markedly reduced PPARc expression and induced p62\ud accumulation, which was counteracted by overexpression of PPARc in TRIB3-knocked down cells. Taken together, we\ud demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo,\ud are modulated by upregulation of PPARc-dependent pathways

Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma

Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells. In this study, we examined whether the PPARc-activated pathway contributed to the antitumor effect of two cannabinoids, D9-tetrahydrocannabinol (THC) and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity and intracellular level of PPARc mRNA and protein, which was abolished by the PPARc inhibitor GW9662. Moreover, genetic ablation with small interfering RNA (siRNA), as well as pharmacological inhibition of PPARc decreased the cannabinoid-induced cell death and apoptosis. Likewise, GW9662 totally blocked the antitumoral action of cannabinoids in xenograft-induced HCC tumors in mice. In addition, PPARc knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62, suggesting that PPARc is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the endoplasmic reticulum stress-related protein tribbles homolog 3 (TRIB3) markedly reduced PPARc expression and induced p62 accumulation, which was counteracted by overexpression of PPARc in TRIB3-knocked down cells. Taken together, we demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo, are modulated by upregulation of PPARc-dependent pathways

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a ?stem-like? state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers ?III-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1?. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1? and VEGF while it restored the levels of E-cadherin and PGC-1?. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring.Fundación Tatiana Pérez de Guzmán el Buen

Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival

2017 American Association for Cancer Research. Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the a1 but not the a2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2þ and requires the Ca2þ/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2þ-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell-cycle arrest, and enhanced cell viability/ survival after etoposide treatment, with both effects being abolished by knockout of AMPK-a1 and a2. The CDK4/6 inhibitor palbociclib also caused G1 arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the a1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-a1 (but not -a2) is amplified in some human cancers. Furthermore, a1-selective inhibitors might enhance the anticancer effects of genotoxic-based therapies

Actuación de las entidades persecutoras de los delitos informáticos en pandemia por COVID-19

Esta presente tesis, tuvo como objetivo general determinar si la actuación de las entidades persecutoras de los delitos informáticos fueron las adecuadas durante pandemia por covid-19, en tal sentido se tomó antecedes nacionales e internacionales y dos teorías bases a fin proponer posibles soluciones al problema que es materia de investigación teniéndose en cuenta la experticia de los entrevistados, quienes laboran en el Ministerio Publico, División de Investigación de Delitos de Alta Tecnología (DIVINDAT) y una letrada independiente. Por otro lado, se destaca que la presente tesis es de enfoque cualitativo de tipo base, con diseño fenomenológico y de método inductivo, teniendo como herramienta de investigación para el procesamiento de análisis datos el programa ATLAS.ti 9. Finalmente, se evidencio en la tesis problemas como la falta de personal capacitado en ambos órganos, así también, la insuficiencia de herramientas digitales y tecnológicos para llevar a cabo una correcta investigación; y finalmente cursos, capacitación por parte del Gobierno Peruano a todo el personal, pues a raíz de la pandemia la Fiscalía Especializada en Ciberdelincuencia y la Divindat no se abastece ante la indagación de los delitos informáticos

A survey of deep learning models in medical therapeutic areas.

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Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self‐renew and often escape therapy. The key metabolic sensor AMP‐activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC

AMPK Causes Cell Cycle Arrest in LKB1-deficient Cells via Activation of CAMKK2

The AMP-activated protein kinase (AMPK) is activated by phosphorylation at Thr172, either by the tumor suppressor kinase LKB1 or by an alternate pathway involving the Ca(2+)/calmodulin-dependent kinase, CAMKK2. Increases in AMP:ATP and ADP:ATP ratios, signifying energy deficit, promote allosteric activation and net Thr172 phosphorylation mediated by LKB1, so that the LKB1-AMPK pathway acts as an energy sensor. Many tumor cells carry loss-of-function mutations in the STK11 gene encoding LKB1, but LKB1 re-expression in these cells causes cell cycle arrest. Therefore, it was investigated as to whether arrest by LKB1 is caused by activation of AMPK or of one of the AMPK-related kinases, which are also dependent on LKB1 but are not activated by CAMKK2. In three LKB1-null tumor cell lines, treatment with the Ca(2+) ionophore A23187 caused a G1-arrest that correlated with AMPK activation and Thr172 phosphorylation. In G361 cells, expression of a truncated, CAMKK2 mutant also caused G1-arrest similar to that caused by expression of LKB1, while expression of a dominant negative AMPK mutant, or a double knockout of both AMPK-α subunits, also prevented the cell cycle arrest caused by A23187. These mechanistic findings confirm that AMPK activation triggers cell cycle arrest, and also suggest that the rapid proliferation of LKB1-null tumor cells is due to lack of the restraining influence of AMPK. However, cell cycle arrest can be restored by re-expressing LKB1 or a constitutively active CAMKK2, or by pharmacological agents that increase intracellular Ca(2+) and thus activate endogenous CAMKK2. IMPLICATIONS: Evidence here reveals that the rapid growth and proliferation of cancer cells lacking the tumor suppressor LKB1 is due to reduced activity of AMPK, and suggests a therapeutic approach by which this block might be circumvented

La mujer peruana: evolución y perspectivas para su desarrollo futuro (1990-2020) región Ayacucho

En el Perú la población femenina y masculina no se encuentran en igualdad de condiciones y es evidente la discriminación y exclusión de las mujeres. Coincidentemente, las regiones con menores índices de desarrollo son las que presentan las mayores brechas de género. La disminución de estas brechas no garantiza el desarrollo de las regiones pero sí contribuye a su mejora, toda vez que esta mejora depende también de otros factores como la pobreza y la discriminación por raza y condición socioeconómica, entre otros. Al existir diversidad de condiciones en las regiones que presenta el Perú se hace preciso el estudio específico en cada una de estas zonas, con la finalidad de conocer las causas de estas brechas de género y a partir de ello plantear políticas que contribuyan a su solución. En tal contexto, la presente investigación se enfoca en la mujer peruana de la región Ayacucho, sintetizando su situación evolutiva demográfica, educativa, de salud, política y económica desde el año 1990 al 2010 y recogiendo sus expectativas personales, dentro diferentes ámbitos, para la siguiente década (2011-2020), así como los obstáculos que encuentran y pudieran encontrar en el cumplimiento de sus objetivos. La investigación tiene un propósito descriptivo y ha utilizado un enfoque cualitativo. La muestra de 27 mujeres ha sido construida utilizando una combinación de las técnicas bola de nieve y máxima variación considerando las siguientes dimensiones: edad, estado civil, nivel educativo, nivel económico, y actividad laboral. Los resultados demuestran una evolución favorable en estas dos últimas décadas en todos los aspectos estudiados. A pesar de ello, existen aún diferencias importantes con otros departamentos y la percepción de obstáculos que limitan el desarrollo de la mujer ayacuchana. Se espera que las recomendaciones efectuadas contribuyan a la mejora de los aspectos negativos que aún se presentan.In Peru, the female and male population is not in equal conditions and the discrimination and exclusion of women is evident. Coincidentally, regions with lower rates of development are those with the largest gender gaps. Closing these gaps does not guarantee the development of the regions but does contribute to its improvement, since this improvement also depends on other factors such as poverty and discrimination by race and socioeconomic status, among others. As there are variety of conditions in the regions of Peru, it is necessary the specific study in each of these areas, in order to determine the causes of these gender gaps and propose policies that contribute to its solution. In this context, this research focuses on the Peruvian woman from Ayacucho region, summarizing the situation evolving demographic, educational, health, political and economic from 1990 to 2011 and collecting their personal expectations, in different areas, for next decade (2011-2020) as well as the obstacles encountered and may encounter in meeting their objectives. The research has a descriptive purpose and has used a qualitative approach. The sample of 27 women has been built using a combination of snowball techniques and maximum variation considering the following dimensions: age, marital status, educational level, income, and work activity. The results show a positive trend in the last two decades in all aspects studied. Nevertheless, there are still important differences with other departments and perceived obstacles limiting women's development in Ayacucho. It is hoped that the recommendations made will contribute to the improvement of the negatives aspects that still occur.Tesi