p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc

Jeong, Jae‐Uk; Kang, Shin‐Sung; Park, Kwan‐Kyu; Chang, Hyeun‐Wook; Magae, Junji; Chang, Young‐Chae

doi:10.1158/1535-7163.mct-09-1159

Cited by 64 publications

(43 citation statements)

References 48 publications

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“…HCT-116 p53 -/-and HCT-116 p21 -/-cells lost both the growth-inhibitory effect and G 0 /G 1 arrest pattern of the cell cycle after DPD treatment. Previous studies have also shown the p21 induction and G 1 arrest by a p53-independent pathway (22) and the p21 involvement in cell growth and cell cycle of HCT-116 cells (23)(24)(25). It has been suggested that DPD induces p21 expression through a p53-independent pathway in colon cancer cells.…”

Section: Discussionmentioning

confidence: 90%

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

et al. 2011

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Abstract. 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane (DPD) induces growth inhibition in human cancer cells. In our previous study, we discovered that DPD irreversibly inhibits the growth of Colo 205 colon cancer cells at the G 0 /G 1 phase and induces cell differentiation. However, the detailed mechanism is still unknown. In this study, we examined the functional importance of p21 and p53 in DPD-induced anticancer effects. We used three isogenic cell lines, HCT-116, HCT-116 p53 -/-and HCT-116 p21 and HCT-116 p53 -/-but not in HCT-116 p21 -/-cells. p21 was required for the DPD-induced in vitro anti-colon cancer effect. The in vivo study also showed that DPD significantly inhibited tumor growth through p21 signaling. Our results clearly demonstrate that DPD-induced in vitro and in vivo anticancer effects through the activation of p21 in HCT-116 cells.

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Section: Discussionmentioning

confidence: 90%

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

et al. 2011

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“…This suggests that both p53-dependent and p53-independent mechanisms may be involved in the up-regulation of Noxa and p21 induced by bortezomib in TRAF3-deficient malignant B cells. Indeed, multiple p53-independent mechanisms of Noxa and p21 induction have been described in the literature, including those dependent on Myc, RelA, p73, or E2F1 [38–42]. Regardless of the detailed mechanisms, the functional consequences of Noxa and p21 up-regulation are clear.…”

Section: Discussionmentioning

confidence: 99%

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

et al. 2016

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Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

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“…It has been reported that p53-independent upregulation of p21 is facilitated by Chk-2 or by downregulation of c-myc (Aliouat-Denis et al 2005;Jeong et al 2010). Russo et al describe that diethylmaleate, an oxidizing agent, can activate p21 in p53-mutated conditions and block the cell cycle in G 1 phase (Russo et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

Chakraborty

Rasool

Kumar

et al. 2016

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Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA-β-gal stains; showed characteristic p21 waf1 upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21 waf1 , confirming that the modulation in p21 waf1 by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21 waf1 expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model.

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p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc

Cited by 64 publications

References 48 publications

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

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