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Salivary Gland Tumors
Published in Dongyou Liu, Tumors and Cancers, 2017
Risk factors for salivary gland tumors include exposure to ionizing radiation (e.g., previous radiotherapy for head and neck neoplasms), rubber product manufacturing, asbestos mining, plumbing, and woodworking. Genetic alterations have been also observed in MEC (chromosome translocation t[11;19][q14–21;p12–13], MECT1-MAML2); ACC and hyalinizing clear cell carcinoma (MYB-NFIB and EWSR1-ATF1 gene fusions, respectively); acinic cell carcinoma, cystadenocarcinoma, and adenocarcinoma NOS (ETV6-NTRK3); and salivary duct carcinoma (6q and 17p/17q mutations, chromosome 7 polysomy, 12q amplification, 9p LOH, methylation of MGMT, DAPK, and RASSF1) [2,4].
MAPK signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Archana Devi, Bhavana Kushwaha, Gopal Gupta
ERK1 and ERK2 are Ser/Thr kinases that participate in the Ras-Raf-MEK-ERK signaling pathway. This signaling is involved in the regulation of a plethora of cellular processes like cell adhesion, cell migration, cell growth, metabolic cycles and transcription of genes (29). Phosphorylation of ERK1/2 at Tyr204/187 and then at Thr202/185 is critical for their activation. While Raf and MEK have limited substrate specificity, ERK1/2 can catalyze the phosphorylation of a number of cytoplasmic and nuclear target proteins (30–32). ERK1/2 mediate the phosphorylation of a variety of substrates from the cytoplasmic and nuclear fractions of a cell including death-associated protein kinase (DAPK), tuberous sclerosis complex 2 (TSC2), RSK, MNK, NF-AT, Elk-1, myocyte enhancer factor 2 (MEF2), c-Fos, c-Myc, STAT3 and several other transcription factors and inhibitory molecules (11). Germ cells and Sertoli cells are known to express ERK1/2, which play a pivotal role in spermatogenesis, including germ cell survival, spermatocyte proliferation and meiotic divisions, as well as the acquisition of sperm motility (21). ERK participates in maintaining the connection between Sertoli and germ cells, especially at the apical ES, where its activity is elevated through phosphorylation at the time of ES disassembly to facilitate spermiation (Figure 10.2). Hence, the phospho-ERK/ERK ratio is higher in the seminiferous epithelium during spermiation (3). Consequently, a reduction in intratesticular testosterone (T) levels by subdermal T and estradiol (E) implants in adult rats promoted loss of germ cells (step 8 spermatids and beyond) from the epithelium due to activation of ERK activity and abrogation of apical ES adhesion (33). Similarly, a dramatic activation of ERK and removal of germ cells was seen in rat epithelium after disruption of apical ES structure by adjudin (1-[2,4-dichlorobenzyl]-1H-indazole-3- carbohydrazide, formerly named AF-2364) (28), which could be inhibited by pretreatment with U0126, a specific inhibitor of upstream ERK kinase MEK (34).TNF-α, mostly secreted by germ cells, has been linked in the regulation of several cellular processes in spermatogenesis, including disruption of BTB through transient activation of ERK and p38MAPK (19), which implies that both ERK and p38MAPK play significant roles in the opening of BTB to aid migration of preleptotene and leptotene spermatocytes from the basal to the adluminal compartment (36). The ERK activation is primarily heralded by the activation of two focal adhesion components present at the apical ES, focal adhesion kinase (FAK) and c-Src, which supports the view that ERK serves as an important downstream signal transducer for the disorganization of the FA-like ES structure (37). The ERK plays critical roles via TGF-β3 in the regulation of adherens junctions of Sertoli cells (34).
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
Tumor cells can also acquire resistance to apoptosis or programmed cell death, which results from a variety of factors. For one, loss of matrix attachment leads to death of epithelial cells, a phenomenon termed anoikis (106). Also, a rapid process of apoptosis (2–8 hr) is evoked by various factors including extracellular factors such as tumor necrosis factor (TNF) family members, including TNF-α, Fas ligand (Fas L; also known as TNFSF6, tumor necrosis factor super family, member 6; APT1 APO1 or CD95) and TNF-related apoptosis-inducing ligand (TRAIL) (107), whereas a slower intrinsic process (8–48 hr) is mediated by intracellular factors such as proapoptotic products of the BCL-2 gene family (108). This slower form of apoptosis is initiated by mitochondrial release of proapoptotic factors and cytochrome C, which can result from translocation of BAX to mitochondria (109). Apoptosis is effected by caspases, which comprise three families of cysteine aspartate proteases (hence caspase) residing in the cyto-sol as inactive zymogens (110). Specific caspases are involved in either the initiation or execution phases of cell death. Members of one family, caspases 8 and 10, associate through a death effector domain with the cell membrane death receptors of TNF-α, Fas L or TRAIL. Another family of caspases, 1, 2, 4, 5, and 9, have a caspase recruiting domain. The downstream effector caspases are 3, 6, and 7, which are activated by members of the other two families. Deregulation of the death receptor pathway to apoptosis is frequent in many types of pediatric tumors due to methylation and gene silencing of CASP8 (111). Apoptosis can be inhibited by prevention of increased mitochondrial permeability transition and/or stabilization of the barrier function of the outer mitochondrial membrane (112) or through interaction with Apaf (apoptosis activation factor)-1 to inhibit activation of caspases (113). Antiapoptotic members of the BCL-2 gene family include BCL-2, BCL-XL, and MCL-1 which encode proteins that prevent release of proapoptotic factors, thereby conferring resistance to apoptosis. Because elevated expression of BCL-2 and BCL-XL results in enhanced cell survival, they are considered to be proto-oncogenes (Table 1a), although in some circumstances BCL-2 inhibits tumorigenesis (114). Inactivating mutations in the proapoptotic BAX and BAK genes are found in some cancers (115), and hence these are considered to be tumor suppressor genes (Table 1b). Another proapoptotic protein is death-associated protein (DAP) which is localized to the cytoskeleton and mediates interferon-γ-induced cell death (116). The gene for DAP kinase (DAPK1) is considered to be a tumor suppressor gene (Table 1b). Activation of RPTKs, including EGFR, ILGF-1R and Met, can alleviate anoikis (117). Overexpression of COX-2 can also inhibit apoptosis (118). Thus, tumor cells can acquire resistance to apoptosis through alteration of a number of signaling pathways, several of which are regulated by p53 (90).
Clinical utility of checkpoint inhibitors against metastatic bladder cancer: overcoming challenges to find a way forward
Published in Expert Opinion on Biological Therapy, 2023
Andreia Bilé-Silva, Antonio Lopez-Beltran, Ana Blanca, Fernando Lopez-Rios, Enrique Gómez-Gómez, Alessia Cimadamore, Rodolfo Montironi, Nuno Vau, Liang Cheng
DAPK1 role in bladder cancer has been investigated. DAPK1 is known to play an important function in apoptosis and autophagy to suppress cancer progression. A preserved expression of DAPK1 in bladder cancer was negatively associated with tumor stage, and a low-level expression of DAPK1 in bladder cancer specimens was associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462). Furthermore, FGFR3 knockdown leads to DAPK1 downregulation in the bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1. Two drugs that inhibit the Raf/MEK pathway, vemurafenib, and trametinib, could possibly reverse the DAPK1-associated gene signature, thus suggesting a new potential therapeutic target [74].
Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ahmed K. Farag, Ahmed H. E. Hassan, Byung Sun Ahn, Ki Duk Park, Eun Joo Roh
Death-Associated Protein Kinase-1 (DAPK1), which controls several functions of the human cell, is well-known for its role in apoptosis, autophagy, and suppressing tumour growth21. However, depending on the cellular context and cellular stimulants, it might operate to promote or suppress cellular growth21–23. Interestingly, DAPK1 Knockdown or inhibition significantly suppressed the growth of the HCC1143, HCC1937, HCC1954 triple-negative breast cancer (TNBC) cell lines by 80–90% suggesting the development of DAPK1 inhibitors to target TNBC24. In another report, silencing DAPK1 by siRNA in HHUA human endometrial adenocarcinoma cell line increased the apoptotic cell death. These results suggest the use of DAPK1 inhibitors for targeting uterine cancers25,26. Besides, ZIP kinase (DAPK3) is activated by DAPK1, which makes DAPK1 inhibitors potential downregulators of ZIP kinase activity27. As the activity of the downstream ZIP kinase is critically required in several cancers including prostate, colon and lung cancers, inhibitors of the upstream DAPK1 activity could be beneficial for the treatment of multiple types of cancer28–30.
Triangle collaboration assessment of autophagy, ER stress and hypoxia in leukemogenesis: a bright perspective on the molecular recognition of B-ALL
Published in Archives of Physiology and Biochemistry, 2021
Fatemeh Feizi, Mehdi Allahbakhshian Farsani, Amin Mirzaeian, Vahide Takhviji, Abbas Hajifathali, Mohammad Hossein Mohammadi
For cell death signalling, DAPK1 mRNA was analysed and it was decreased in 76 percentages of the patients. This finding was confirmed by many publications; Sarhan et al. exhibited the DAPK1 promoter hypermethylation in acute myeloid leukemia (AML), ALL and CLL groups compared with the control subjects (Sarhan et al.2016). Other researches demonstrated that DAPK1 function and expression might be decline in several solid tumors including breast, ovarian and liver cancer and so on (Li et al.2017). Consequently, DAPK1 down-regulation could be defensible, owning to its crucial role in controlling the cell cycle, programed cell death and metastasis repression (Singh et al.2016, Nikbakht et al.2017).