thapsigargin and cordycepin

The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3'-deoxyadenosine (cordycepin) towards cell survival. 3'-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3'-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2α signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2α, and dephosphorylation of eIF2α by salubrinal mimicked the anti-apoptotic effect of 3'-deoxyadenosine. Unexpectedly, although 3'-deoxyadenosine caused activation of eIF2α, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3'-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3'-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3'-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders.

Topics: Animals; Apoptosis; Biomarkers; Cell Line; Cell Survival; Deoxyadenosines; eIF-2 Kinase; Heat-Shock Proteins; Humans; Membrane Proteins; Mice; Protein Serine-Threonine Kinases; Rats; Signal Transduction; Thapsigargin; Transcription Factor CHOP; Tunicamycin; Unfolded Protein Response

Cordycepin (3'-deoxyadenosine) is an adenosine analog, isolated from Cordyceps militaris, and it has been used as an anticancer and anti-inflammation ingredient in traditional Chinese medicine. We investigated the effects of cordycepin (3'-deoxyadenosine) on human platelet aggregation, which was induced by thapsigargin, a tumor promoter, and determined the cytosolic free Ca2+ levels ([Ca2+]i) (an aggregation-stimulating molecule) and cyclic-guanosine monophosphate (cGMP) (an aggregation-inhibiting molecule). Cordycepin inhibited thapsigargin-induced platelet aggregation in a dose-dependent manner, and it clearly reduced the levels of [Ca+]i, which was increased by thapsigargin (1 microM) or U46619 (3 microM). Cordycepin also increased the thapsigargin-reduced cGMP levels. Accordingly, our data demonstrated that cordycepin may have a beneficial effect on platelet aggregation-mediated thrombotic diseases through the [Ca2+]i-regulating system such as cGMP.

Topics: Cordyceps; Deoxyadenosines; Dose-Response Relationship, Drug; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Thapsigargin