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Role of High-Risk Human Papillomaviruses in Breast Carcinogenesis
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
The viral E6 protein complements the role of E7 and is thought to prevent the induction of apoptosis in response to unscheduled S-phase entry mediated by E7 (Ghittoni et al. 2010). Although the association of E6 with p53 and the inactivation of p53-mediated growth suppression and/or apoptosis have been well documented, E6 can also associate with other proapoptotic proteins including Bcl-2 homologous antagonist/killer (Bak) (Thomas and Banks 1998) and Bcl-2-assoicated X protein (Bax) (Magal et al. 2005). Consequently, the presence of E6 is considered a predisposing factor in the development of HPV-associated cancers, allowing the accumulation of chance errors in host cell DNA to go unchecked. The E6 protein of high-risk HPV types can also stimulate cell proliferation independently of E7 through its C-terminal PDZ-ligand domain (Thomas et al. 2002). E6-PDZ binding is sufficient to mediate suprabasal cell proliferation (Nguyen et al. 2003a, 2003b) and may contribute to the development of metastatic tumors by disrupting normal cell adhesion.
Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players
Published in Scandinavian Journal of Gastroenterology, 2022
Lei Yu, Miao-Miao Zhang, Ji-Guang Hou
An imbalance in the pro‐ and anti‐apoptotic protein levels is a key cause for the progression of CRC, with an elaborate interaction of B-cell lymphoma-2 (Bcl‐2), B-cell lymphoma-extra large (Bcl-xL), BCL2 associated X (Bax) and the IAP family members [17]. The process of transformation from benign adenoma to the malignant lesions involves the participation of these apoptotic proteins, together with an activated outer membrane permeability and cytochrome c release. A modulated expression of the BCL-2 family proteins, comprising reduced Bcl2 and Myeloid leukemia 1 (MCL-1) and amplified B-cell lymphoma-extra large (Bcl-xL) and BCL-W, promotes CRC pathogenesis and an attenuated sensitivity to therapy [18]. A BC-XL-mediated chemo-resistance to the colon cancer stem cells and differentiated colon cells has also been reported [18]. A reduced proteasomal degradation of MCL-1, owing to its altered binding to Glycogen synthase kinase-3β, and the mutation or reduced functioning of E3 ubiquitin ligase, FBW7 or USP9X, diminish the efficacy of CRC chemosensitivity [18]. In terms of effector proteins, Bax frameshift mutations and reduced Bcl-2 homologous antagonist/killer (BAK) expression, together with the down-regulated BAX interacting factor-1 suppress apoptosis in CRC [18]. An altered expression of the BH3-only proteins, particularly p53 upregulated modulator of apoptosis (PUMA) and BH3 interacting-domain death (BID), and augmented BAD phosphorylation have also been reported, along with mutations in Bad gene and promoter methylation in Hrk [18].
Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry
Published in Xenobiotica, 2019
Riya Shrestha, Jung Jae Jo, DooHyun Lee, Taeho Lee, Sangkyu Lee
Leelamine (Figure 1), a dehydroabietylamine derivative of dehydroabietic acid, is found in the resins of pine trees (Kovaleva et al., 2017). It is a pyruvate dehydrogenase kinase 4 (PDK4) inhibitor and has been found to exhibit hypoglycemic activity in ob/ob mice and inhibit glyceroneogenesis in isolated adipocytes by activating the pyruvate dehydrogenase complex (PDC) (Cadoudal et al., 2008; Jeoung & Harris, 2010). Leelamine as a drug has been of considerable interest recently because it has been effective in the treatment of melanoma by disrupting cholesterol homeostasis in cancer cells (Gowda et al., 2017; Kuzu et al., 2014). It exhibits a strong anticancer effect on human breast cancer cell lines by generating reactive oxygen species and inducing B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak)-dependent apoptosis (Sehrawat et al., 2017). Moreover, our previous study in mice showed that leelamine is a potent and selective inducer of CYP2B activity, but has a low oral bioavailability of 7.6% (Sim et al., 2015; Song et al., 2013).
Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells, affecting PI3K-AKT-mTOR and Ras-MAPK pathways
Published in Journal of Immunotoxicology, 2018
Francisco Gallardo-Vera, Miguel Tapia-Rodriguez, Daniel Diaz, Teresa Fortoul van der Goes, Luis F. Montaño, Erika P. Rendón-Huerta
Mouse monoclonal anti-human SHP1 (1:100), AF 647-anti-p-MEK1/2 (Mitogen-activated protein kinase kinase, Ser218/222) (1:50), PE-anti-p-mTOR (Ser2448) (1:400), anti-PTEN (1:400), and anti-MEK-1 (1:50) were all obtained from BD PhosFlow. Rabbit anti-human Bax (Bcl-2-associated X protein, 1:100) and rabbit monoclonal DyLight AF 488-anti-human BAD (Bcl-2-associated death promoter, 1:800) were bought from Abcam (San Francisco, CA, USA). Mouse monoclonal AF 488-anti-human BAK (Bcl-2 homologous antagonist/killer, NBP1–74026AF488, 1:400) was purchased from Novus Biologicals, LLC (Littleton, CO, USA). As secondary antibodies, Cy5-conjugated goat anti-rabbit IgG (H + L, 1:800) and/or AF-488-labeled goat anti-mouse IgG (H + L, 1:400) were used (ThermoFisher Scientific Inc., Waltham, MA, USA).