Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time-dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down-regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer.
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PMID:Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling. 2722 22

DDEFL1 is related to maintaining a limiting amount of ARF6 in GTP-loaded form by accelerating its GTP hydrolysis activity, which has been implicated in hepatocellular cancer pathogenesis and lung cancer development. We investigated DDEFL1 expression in breast cancer and paired normal breast tissues by immunohistochemistry and found that DDEFL1 expression was significantly associated with tumor size, lymph node metastasis, high content of elastosis and TNM stage but not with menopausal status or age. We detected the mRNA and protein expression of DDEFL1 in breast cancer cell lines by Western blotting and quantitative real-time PCR (qRT-PCR). DDEFL1 was obvious in MDA-MB-435s and MDA-MB-231 but very weak in ZR-75-1. Further experiments were conducted to evaluate the effect of DDEFL1 small interfering RNA (siRNA) transfection on the biological behavior of MDA-MB-231. After transfection, the effects of DDEFL1 inhibition on expression of mRNA and protein were also analyzed by Western blotting and qRT-PCR. Increased apoptosis and invasive ability, decreased cellular proliferation was found in MDA-MB-231 with successful DDEFL1 siRNA transient transfection (p < 0.05). Western blotting and qRT-PCR results showed that the DDEFL1 inhibition up-regulated Caspase-3, Apaf-1, cytochrome c, and Bax expression and down-regulated Bcl-2 expression. The DDEFL1 inhibition also down-regulated the mRNA and protein expression of Rho, CDC42 and Rac1. Our study provided a functional linkage through DDEFL1 with breast cancer biological behaviours by Rho GTPases. Possible implication of our main finding for the DDEFL1 role in breast cancer and the downstream signaling pathways for the treatment of breast cancer.
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PMID:DDEFL1 correlated with Rho GTPases activity in breast cancer. 2934 42


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