Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-0024 | DOI Listing |
Phytomedicine
January 2025
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Changle West Street 15, Xi'an, Shaanxi, 710032, China. Electronic address:
Background: The pathogenesis of neuropathic pain is complex and lacks effective clinical treatment strategies. Medical plants and herbal extracts from traditional Chinese medicine with multi-target comprehensive effects have attracted great attention from scientists.
Purpose: To investigate the pharmacological active components and mechanism underlying the anti-neuralgia effect of classic analgesic formulas Duhuo Jisheng Mixture (DJM).
Pharmaceuticals (Basel)
January 2025
Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea.
: , a bacterium residing in hair follicles, triggers acne by inducing monocyte-mediated inflammatory cytokine production. Gedunin, a limonoid derived from (commonly known as neem), is renowned for its antifungal, antimalarial, anticancer, anti-inflammatory, and neuroprotective effects. However, its role in mitigating -induced skin inflammation remains unexplored.
View Article and Find Full Text PDFInt J Mol Sci
January 2025
Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain.
Class IA PI3K p110δ and p110α subunits participate in TCR and costimulatory receptor signals involved in T cell-mediated immunity, but the role of p110α is not completely understood. Here, we analyzed a mouse model of the Cre-dependent functional inactivation of p110α (kinase dead) in T lymphocytes (p110αKD-T, KD). KD mice showed increased cellularity in thymus and spleen and altered T cell differentiation with increased number of CD4CD8 DP thymocytes, enhanced proportion of CD4 SP lymphocytes linked to altered apoptosis, lower Treg cells, and increased AKT and ERK phosphorylation in activated thymocytes.
View Article and Find Full Text PDFBiomolecules
January 2025
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally, with a persistently low five-year survival rate of only 14-17%. High rates of metastasis contribute significantly to the poor prognosis of NSCLC, in which inflammation plays an important role by enhancing tumor growth, angiogenesis, and metastasis. Targeting inflammatory pathways within cancer cells may thus represent a promising strategy for inhibiting NSCLC metastasis.
View Article and Find Full Text PDFCancers (Basel)
January 2025
School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar 751024, India.
The complex signaling network within the breast tumor microenvironment is crucial for its growth, metastasis, angiogenesis, therapy escape, stem cell maintenance, and immunomodulation. An array of secretory factors and their receptors activate downstream signaling cascades regulating breast cancer progression and metastasis. Among various signaling pathways, the EGFR, ER, Notch, and Hedgehog signaling pathways have recently been identified as crucial in terms of breast cancer proliferation, survival, differentiation, maintenance of CSCs, and therapy failure.
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