FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway
| Autor: | Mohammad Aminur Rahman, Dong M. Shin, Fadlo R. Khuri, Abedul Haque, Zhuo Georgia Chen, James R. Fuchs, A.R.M. Ruhul Amin |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Curcumin Lung Neoplasms Poly ADP ribose polymerase Sulforhodamine B Apoptosis Biology Article chemistry.chemical_compound Annexin In vivo Cell Line Tumor medicine Humans Lung cancer Tumor Suppressor Proteins Nuclear Proteins Tumor Protein p73 medicine.disease Molecular biology DNA-Binding Proteins Gene Expression Regulation Neoplastic Receptors TNF-Related Apoptosis-Inducing Ligand Oncology chemistry Cell culture Cancer research Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Cancer Letters. 363:166-175 |
| ISSN: | 0304-3835 |
| Popis: | Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5–10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase-8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by post-transcriptional regulation of DR5 through activation of protein tyrosine phosphatase(s). |
| Databáze: | OpenAIRE |
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