We reported previously that panaxydol, a component of Panax ginseng roots, induced mitochondria-mediated apoptosis preferentially in transformed cells. This study demonstrates that EGFR activation and the resulting ER stress mediate panaxydolinduced apoptosis, and that panaxydol suppresses in vivo tumor growth in syngeneic and xenogeneic mouse tumor models. In addition, we elucidated that CaMKII and TGF-b-activated kinase (TAK1) Ginsenoside and C17 polyacetylenic compounds of Panax ginseng (P. ginseng C.A. Meyer, Korean ginseng) roots possess anticancer activities. [1][2][3][4] It has been shown that panaxydol (heptadeca-1-en-4,6-diyn-9,10-epoxy-3-ol), one of the C17 polyacetylenic compounds of P. ginseng, induces G1 cell cycle arrest or apoptosis in cancer cells depending on the concentration. 4,5 We also previously reported that the mechanisms of panaxydol-induced apoptosis involve a rapid increase in the cytoplasmic Ca 21 concentration ([Ca 21 ]c), activating NADPH oxidase via p38/JNK. NADPH oxidase activation induces oxidative stress and triggers mitochondria-dependent apoptosis. 5Transfer of excess Ca 21 from the endoplasmic reticulum (ER) to the mitochondria is an important mechanism in mitochondria-dependent apoptosis. It is postulated that ER Ca 21 is transferred via the mitochondria-associated ER

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The importance of proteostasis in preventing cellular senescence has been well recognized. However, the exact mechanism by which the loss of proteostasis or endoplasmic reticulum (ER) stress induces cellular senescence remains unclear. We report that ER stress mediates cellular senescence through the activating transcription factor (ATF)6α branch of the unfolded protein response (UPR). Cellular senescence was induced by the abrogation of neighbor of breast cancer (BRCA)1 gene (NBR1). NBR1 abrogation‐induced senescence was p53 dependent and observed in both transformed and nontransformed human cell lines: MCF‐7, Caki‐1, and MRC‐5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidase was activated in turn by p38, and the resulting oxidative stress triggered ER stress. It was found that ER stress mediated cellular senescence through the UPR sensor ATF6α. Knockdown of ATF6α prevented senescence, whereas ATF6α overexpression triggered it. The transcriptional activity of ATF6α was important. The ER stress‐ATF6α axis also mediated cellular senescence induced by H‐RasV12 overexpression and UV irradiation, suggesting a common role of this axis in senescence induction. In summary, we presented an evidence for the novel role of the ER stress‐ATF6α axis in cellular senescence.—Kim, H. S., Kim, Y., Lim, M. J., Park, Y.‐G., Park, S. I., Sohn, J. The p38‐activated ER stress‐ATF6α axis mediates cellular senescence. FASEB J. 33, 2422–2434 (2019). http://www.fasebj.org

Background: IL-4 can directly inhibit growth of several tumor cell types, but the molecular mechanism is not known. Results: IL-4 induces senescence by increasing p21 WAF1/CIP1 expression through STAT6 and p38 MAPK. Conclusion: STAT6 and p38 MAPK play important roles in senescence induction by IL-4. Significance: This is the first report of cellular senescence induction by IL-4 and the responsible mechanism.