Ligand-free estrogen receptor activity complements IGF1R to induce the proliferation of the MCF-7 breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Ligand-dependent activation of the estrogen receptor (ER) as well as of the insulin-like growth factor type 1 (IGF1R) induces the proliferation of luminal breast cancer cells. These two pathways cooperate and are interdependent. We addressed the question of the mechanisms of crosstalk between the ER and IGF1R.</p> <p>Methods</p> <p>We evaluated the mitogenic effects of estradiol (E2; agonist ligand of ER) and of insulin (a ligand of IGF1R) in the MCF-7 cells by flow cytometry and by analyzing the cell levels of cell cycle-related proteins (immunoblotting) and mRNA (RT-QPCR). To verify the requirement for the kinase activity of Akt (a downstream target of IGF1R) in the mitogenic action of estradiol, we used shRNA strategy and shRNA-resistant expression vectors.</p> <p>Results</p> <p>The activation of the ER by E2 is unable to induce the cell cycle progression when the phosphatidyl inositol-3 kinase (PI3K)/Akt signaling is blocked by a chemical inhibitor (LY 294002) or by shRNA targeting Akt1 and Akt2. shRNA-resistant Akt wild-type constructs efficiently complemented the mitogenic signaling activity of E2 whereas constructs with inactivated kinase function did not. In growth factor-starved cells, the residual PI3K/Akt activity is sufficient to complement the mitogenic action of E2. Conversely, when ER function is blocked by the antiestrogen ICI 182780, IGF1R signaling is intact but does not lead to efficient reinitiation of the cell cycle in quiescent, growth factor-starved MCF-7 cells. The basal transcription-promoting activity of ligand-free ER in growth factor-starved cells is sufficient to complement the mitogenic action of the IGF1R-dependent signaling.</p> <p>Conclusions</p> <p>The basal ER activity in the absence of ligand is sufficient to allow efficient mitogenic action of IGF1R agonists and needs to be blocked to prevent the cell cycle progression.</p

The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy

The c-kit tyrosine kinase inhibitor STI571 exhibits a substantial therapeutic activity in patients with chronic myeloid leukemia and gastrointestinal stromal tumors respectively associated with constitutive activation of the BCR-ABL and c-kit tyrosine kinases. Human colorectal tumors also express the c-kit proto-oncogene. The present study focuses on the anticancer activity of STI571 in human colorectal tumor cells in vitro and in vivo. The c-kit receptor was identified as a M-r 145,000 immunoreactive band in human colon cancer cells HT29, HCT8/S11, and HCT116. Cellular invasion induced by 10 ng/ml stem cell factor (EC50 = 3 ng/ml) in HT29 cells was blocked by 1 mum STI571 (IC50 = 56 nM) and pharmacological inhibitors of several oncogenic signaling pathways, namely, phosphatidylinositol 3-kinase (LY294002), Rho GTPases (Clostridium botulinum exoenzyme C3 transferase), and Rho-kinase (Y27632). STI571 inhibited HT29 cell proliferation (IC50 = 6 muM) and induced apoptosis in vitro. These cellular effects were associated with a decrease in tumor growth. We also demonstrated that stem cell factor is a proangiogenic factor in vivo and in vitro. These encouraging results warrant further preclinical investigations and clinical trials on the use of the e-kit inhibitor STI571 as a chemotherapeutic agent in colon cancer prevention and in treatment of advanced colorectal cancers associated with liver metastases

Occurrence of synanthropic triatomines (Hemiptera: Reduviidae) in the Federal District of Brazil

INTRODUCTION: Entomological surveillance of Chagas disease in the Federal District of Brazil (DF), has recorded the following triatomine species: Panstrongylus megistus, P. geniculatus, P. diasi, Rhodnius neglectus, Triatoma pseudomaculata, and T. sordida. We aimed to analyze the spatial and temporal occurrence of triatomine species collected in DF, and their indices of natural infection with trypanosomes. METHODS: The Health State Secretariat of DF recorded triatomines between 2002 and 2010 in 20 administrative regions. This retrospective analysis considered the number of adults and nymphs of each species collected and infected in both intradomicile and peridomicile. RESULTS: A total of 754 triatomines were collected in 252 reported domiciles. Panstrongylus megistus was the most frequent species (65%), followed by T. pseudomaculata (14%). Of the 309 examined insects, only 3 (1%) specimens of P. megistus were infected with flagellates morphologically similar to Trypanosoma cruzi. The spatial occurrence indicated a higher diversity of triatomines and frequency of T. sordida in rural areas. Moreover, there was a predominance of P. megistus in urban areas. The number of records of P. megistus in the rainy season was two times higher than that during the dry season. The largest number of triatomines was collected in November. CONCLUSIONS: The presence of P. megistus specimens infected with trypanosomes in domiciles, shows the potential risk of human infection in DF. Thus, it is essential to continue entomological surveillance, intensifying it in the rainy season and in regions of greater occurrence