scholarly journals The Pivotal Role of PAO in CDK Inhibitors (Roscovitine and Purvalanol)- Triggered Apoptosis in PUMA Null HCT116 Colon Cancer Cells

2021 ◽  
pp. 1-10
Author(s):  
Ajda Coker-Gurkan ◽  
Ajda Coker-Gurkan ◽  
Burcu Ayhan-Sahin
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cyclin B1 ◽  
Mapk Signaling ◽  
Cdk Inhibitors ◽  
Colon Cancer Cells ◽  
Drug Induced ◽  
Induced Apoptosis

Background: Cycline-dependent kinase inhibitors (CDKi); roscovitine and purvalanol, are promising anti-cancer drugs due to their strong anti-proliferative effectiveness due to activation of PA catabolism. Besides transforming acetylated spermine and spermidine into spermidine and putrescine, respectively, polyamine oxidase (PAO) also generates hydrogen peroxide in high concentrations as a by-product. PAO was assumed as a pivotal key molecule during drug-induced apoptosis in cancer cells. Our aim is to reveal the role of PAO action in CDKi-triggered apoptosis in Puma knock-out HCT116 colon cancer cells. Methods: HCT116 wt and HCT116 Puma-/- cells were treated with Roscovitine and Purvalanol and cell viability and apoptosis were determined. Protein was isolated from treated and untreated cells and key molecules of cell cycle control and polyamine pathways were investigated at translational level. Polyamine content was determined by HPLC for all conditions. MDL-72527 was used as a PAO inhibitor and apoptotic cell death was analysed. Results: Roscovitine and purvalanol induced apoptosis and increased the cytotoxic responses in HCT116 wt and HCT116 Puma-/- colon carcinoma cell lines by modulating CDK1, 4, cyclin-B1, D3. Both, CDKi altered intrinsic apoptotic pathways in HCT116 wt. Whereas, drug-induced apoptosis occurred caspase-independent in Puma-/- colon cancer cells. Roscovitine and purvalanol up-regulated polyamine catabolic enzymes, whereas CDK inhibitors decreased the polyamine levels in HCT116 wt and HCT116 Puma-/- colon cancer cells. In addition, PAO inhibitor MDL72527 prevented drug-induced apoptosis. Conclusion: PAO expression profile might be a critical target in CDK inhibitors-triggered apoptosis in HCT116 colorectal cancer cells. Thus, MAPK signaling pathway relations with cell cycle and polyamine catabolic pathway investigations are in progress.

CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe

2008 ◽  
Vol 294 (5) ◽  
pp. G1235-G1244 ◽  
Author(s):  
Gopalan Natarajan ◽  
Satish Ramalingam ◽  
Ilangovan Ramachandran ◽  
Randal May ◽  
Lurdes Queimado ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Caspase 3 ◽  
Cyclin B1 ◽  
Mitotic Catastrophe ◽  
Prostaglandin E ◽  
Colon Cancer Cells ◽  
Induced Apoptosis

Prostaglandin E2 (PGE2) is a potent inhibitor of ionizing radiation (IR)-induced cell death. Exposure of colon cancer cells to IR leads to increased CUGBP2 expression. Therefore, we tested the hypothesis that PGE2 radioprotects colon cancer cells by inhibiting CUGBP2 expression. Exposure of HCT-116 cells to γ-IR (0–12 Gy) resulted in a dose-dependent reduction in cell growth and an increase in the G2-M phase of the cell cycle. Western blot analyses demonstrated increased levels of activated caspase 9 and caspase 3. In addition, whereas Bax expression is increased, that of Bcl-2 and Bcl-xL was reduced. Further analyses demonstrated increased activation of Chk1 and Chk2 kinases, coupled with higher levels of nuclear cyclin B1 and Cdc2. Pretreatment with PGE2 suppressed the activation of caspase 3 and caspase 7 and inhibited Bax expression. In addition, PGE2 treatment restored growth and colony formation to control levels. IR significantly upregulated the expression of CUGBP2 in the cells, which was suppressed when cells were pretreated with PGE2. Ectopic overexpression of CUGBP2 also induced apoptosis. Furthermore, it reversed the PGE2-mediated protection from IR-induced mitotic catastrophe. Furthermore, there was an increase in nuclear localization of cyclin B1 and Cdc2 coupled with increased phosphorylation of p53, Chk1, Chk2, and Cdc25c proteins. Cell cycle analysis also demonstrated increased G2-M transition. In contrast, siRNA-mediated suppression of CUGBP2 expression restored normal cell cycle progression and decreased IR-induced apoptosis. Taken together, these data demonstrate that PGE2 protects colon cancer cells from IR-induced mitotic catastrophe in part through suppression of CUGBP2 expression.

scholarly journals Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 97 ◽  
Author(s):  
Ming-Shun Wu ◽  
Chih-Chiang Chien ◽  
Ganbolor Jargalsaikhan ◽  
Noor Andryan Ilsan ◽  
Yen-Chou Chen
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
B Cell Lymphoma ◽  
Human Colon ◽  
Cyclin B1 ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Jnk Inhibitors ◽  
Induced Apoptosis ◽  
Human Colon Cancer Cells

Microtubule-targeting agents (MTAs) are widely used in cancer chemotherapy, but the therapeutic responses significantly vary among different tumor types. Protein kinase RNA-like endoplasmic reticular (ER) kinase (PERK) is an ER stress kinase, and the role of PERK in the anticancer effects of MTAs is still undefined. In the present study, taxol (TAX) and nocodazole (NOC) significantly induced apoptosis with increased expression of phosphorylated PERK (pPERK; Tyr980) in four human colon cancer cell lines, including HCT-15, COLO205, HT-20, and LOVO cells. Induction of G2/M arrest by TAX and NOC with increases in phosphorylated Cdc25C and cyclin B1 protein were observed in human colon cancer cells. Application of the c-Jun N-terminal kinase (JNK) inhibitors SP600125 (SP) and JNK inhibitor V (JNKI) significantly reduced TAX- and NOC-induced apoptosis and G2/M arrest of human colon cancer cells. Interestingly, TAX- and NOC-induced pPERK (Tyr980) protein expression was inhibited by adding the JNK inhibitors, SP and JNKI, and application of the PERK inhibitor GSK2606414 (GSK) significantly reduced apoptosis and G2/M arrest by TAX and NOC, with decreased pPERK (Tyr980) and pJNK, phosphorylated Cdc25C, and Cyc B1 protein expressions in human colon cancer cells. Decreased viability by TAX and NOC was inhibited by knockdown of PERK using PERK siRNA in COLO205 and HCT-15 cells. Disruption of the mitochondrial membrane potential and an increase in B-cell lymphoma-2 (Bcl-2) protein phosphorylation (pBcl-2; Ser70) by TAX and NOC were prevented by adding the PERK inhibitor GSK and JNK inhibitor SP and JNKI. A cross-activation of JNK and PERK by TAX and NOC leading to anti-CRC actions including apoptosis and G2/M arrest was first demonstrated herein.

scholarly journals Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

2008 ◽  
Vol 76 (2) ◽  
pp. 198-207 ◽  
Author(s):  
José M. Escandell ◽  
Pawan Kaler ◽  
M. Carmen Recio ◽  
Takehiko Sasazuki ◽  
Senji Shirasawa ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Colon Cancer Cells ◽  
Induced Apoptosis

scholarly journals The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

2020 ◽  
Author(s):  
Zahra Payandeh ◽  
Abbas Pirpour Tazehkand ◽  
Behzad Mansoori ◽  
Vahid Khaze ◽  
Milad Asadi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Potential Role ◽  
Related Factor ◽  
Colon Cancer Cells ◽  
Novel Approach ◽  
Nrf2 Signaling Pathway ◽  
Ic50 Values ◽  
Induced Apoptosis

Abstract Background: Nuclear factor−erythroid 2−related factor 2 (Nrf2) has a key function in promoting chemoresistance in various cancers. PD-L1 is one of the downstream targets of Nrf2 signaling pathway, having some beneficial impacts on tumors growth by inhibition of the immune system. The aim of this study was to investigate the potential role of Nrf2- PD- L1 axis in the promotion of oxaliplatin resistance in colon cancer cells. Result: Our data revealed that Nrf2 and PD-L1 mRNA expressions were markedly higher in tumor tissues compared to margin tissues. PD-L1 mRNA expression level was also increased in the resistant cells. However, Nrf2 expression was decreased and increased in SW480/Res and LS174T/Res cells, respectively. Nrf2 inhibition through siRNA in SW480/Res and LS174T/Res decreased the IC50 values of oxaliplatin. Inhibition of Nrf2 significantly increased oxaliplatin-induced apoptosis and reduced migration in SW480/Res cells when accompanied with oxaliplatin. Conclusion: Our study suggests that effective inhibition of Nrf2/PD-L1 signaling pathways can be considered as a novel approach to improve oxaliplatin efficacy in colon cancer patients.

scholarly journals α-Hederin Arrests Cell Cycle at G2/M Checkpoint and Promotes Mitochondrial Apoptosis by Blocking Nuclear Factor-κB Signaling in Colon Cancer Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Dongdong Sun ◽  
Weixing Shen ◽  
Feng Zhang ◽  
Huisen Fan ◽  
Jiani Tan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Cyclin B1 ◽  
New Drugs ◽  
Nuclear Factor ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cells

Colon cancer represents the third most common malignancy worldwide. New drugs with high efficaciousness and safety for the treatment of colon cancer are urgently needed in clinical context. Here, we were aimed to evaluate the antitumor activity of the natural compound α-hederin in human colon cancer cells. We treated SW620 cells with interleukin-6 (IL-6) in vitro to mimic the paracrine inflammatory microenvironment of tumor cells. α-Hederin concentration dependently reduced the viability of IL-6-stimulated SW620 cells. α-Hederin increased the number of IL-6-stimulated SW620 cells at the G2/M phase and reduced the mRNA and protein expression of cyclin B1 and CDK1. Moreover, α-hederin induced apoptosis and loss of mitochondrial membrane potential in IL-6-stimulated SW620 cells. α-Hederin downregulated Bcl-2 expression, upregulated Bax expression, and promoted cytochrome c release from mitochondria into cytoplasm. Additionally, α-hederin elevated the levels of cleaved-caspase-9, cleaved-caspase-3, and cleaved-PARP, but had little effects on the levels of cleaved-caspase-8. Moreover, α-hederin prevented the nuclear translocation of nuclear factor-κB (NF-κB) and reduced the phosphorylation of IκBα and IKKα, suggesting the blockade of NF-κB signaling. NF-κB inhibitor PDTC not only produced similar proapoptotic effects on IL-6-stimulated SW620 cells as α-hederin did, but also synergistically enhanced α-hederin’s proapoptotic effects. Furthermore, α-hederin inhibited the phosphorylation of ERK in IL-6-stimulated SW620 cells, which was involved in α-hederin blockade of NF-κB nuclear translocation. Altogether, α-hederin suppressed viability, induced G2/M cell cycle arrest, and stimulated mitochondrial and caspase-dependent apoptosis in colon cancer cells, which were associated with disruption of NF-κB and ERK pathways, suggesting α-hederin as a promising candidate for intervention of colon cancer.

Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells

2018 ◽  
Vol 45 (6) ◽  
pp. 2175-2184 ◽  
Author(s):  
Elif Damla Arisan ◽  
Zehragül Ergül ◽  
Gülnihal Bozdağ ◽  
Özge Rencüzoğulları ◽  
Ajda Çoker-Gürkan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Mapk Signaling ◽  
Colon Cancer Cells ◽  
Signaling Axis ◽  
Hct 116 ◽  
Induced Apoptosis

Translation inhibition during cell cycle arrest and apoptosis: Mcl-1 is a novel target for RNA binding protein CUGBP2

2008 ◽  
Vol 294 (4) ◽  
pp. G1025-G1032 ◽  
Author(s):  
Dharmalingam Subramaniam ◽  
Gopalan Natarajan ◽  
Satish Ramalingam ◽  
Ilangovan Ramachandran ◽  
Randal May ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Rna Binding ◽  
Mrna Translation ◽  
Cyclin B1 ◽  
Colon Cancer Cells ◽  
Translation Inhibition ◽  
M Phase ◽  
Hct 116

CUGBP2, a translation inhibitor, induces colon cancer cells to undergo apoptosis. Mcl-1, an antiapoptotic Bcl-2 family protein, interferes with mitochondrial activation to inhibit apoptosis. Here, we have determined the effect of CUGBP2 on Mcl-1 expression. We developed a HCUG2 cell line by stably expressing CUGBP2 in the HCT-116 colon cancer cells. HCUG2 cells demonstrate decreased levels of proliferation and increased apoptosis, compared with HCT-116 cells. Flow cytometry analysis demonstrated higher levels of cells in the G2-M phase. Western blot analyses demonstrated that there was decreased Bcl-2 and Mcl-1 protein but increased expression of Bax, cyclin B1, and Cdc2. Immunocytochemistry also demonstrated increased levels of cyclin B1 and Cdc2 in the nucleus of HCUG2 cells. However, there was colocalization of phosphorylated histone H3 with transferase-mediated dUTP nick-end labeling (TUNEL). Furthermore, immunostaining for α-tubulin demonstrated that there was disorganization of microtubules. These data suggest that CUGBP2 expression in HCUG2 cells induces the cells to undergo apoptosis during the G2-M phase of the cell cycle. We next determined the mechanism of CUGBP2-mediated reduction in Mcl-1 expression. Mcl-1 protein, but not Mcl-1 mRNA, was lower in HCUG2 cells, suggesting translation inhibition. CUGBP2 binds to Mcl-1 3′-untranslated region (3′-UTR) both in vitro and in HCUG2 cells. Furthermore, CUGBP2 increased the stability of both endogenous Mcl-1 and luciferase mRNA containing the Mcl-1 3′-UTR. However, luciferase protein expression from the luciferase-Mcl-1 3′-UTR mRNA was suppressed. Taken together, these data demonstrate that CUGBP2 inhibits Mcl-1 expression by inhibiting Mcl-1 mRNA translation, resulting in driving the cells to apoptosis during the G2 phase of the cell cycle.

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