Abstract:Lung cancer has the highest incidence and mortality rate worldwide among all malignancy-associated mortalities, of which non-small cell lung cancer accounts for 80% of all cases. Resistance against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) develops following 8–12 months of disease progression, and is a critical issue. HCC827 cell lines with resistance to EGFR-TKIs were successfully screened. The half maximal inhibitory concentration values were 1,000-fold higher than the values fo… Show more
“…5C). The induction of Bcl-2 expression in the H460-overexpressing IKKα cells is a marker of enhanced malignancy, as it has been found that Bcl-2 is markedly increased in lung cancer patient biopsies; additionally, its overexpression has been related with resistance against EGFR-TK inhibitors [27]. Fig.…”
Lung cancer is the leading worldwide cause of cancer mortality, however, neither curative treatments nor substantial prolonged survival has been achieved, highlighting the need for investigating new proteins responsible for its development and progression. IKKα is an essential protein for cell survival and differentiation, which expression is enhanced in human non-small cell lung cancer (NSCLC) and correlates with poor patient survival, appearing as a relevant molecule in lung cancer progression. However, there are not conclusive results about its role in this type of cancer. We have recently found that IKKα performs different functions and activates different signaling pathways depending on its nuclear or cytoplasmic localization in tumor epidermal cells. In this work, we have studied the involvement of IKKα in lung cancer progression through the generation of lung cancer cell lines expressing exogenous IKKα either in the nucleus or in the cytoplasm. We demonstrate that IKKα signaling promotes increased cell malignancy of NSCLC cells as well as lung tumor progression and metastasis in either subcellular localization, through activation of common protumoral proteins, such as Erk, p38 and mTor. But, additionally, we found that depending on its subcellular localization, IKKα has non-overlapping roles in the activation of other different pathways known for their key implication in lung cancer progression: while cytoplasmic IKKα increases EGFR and NF-κB activities in lung tumor cells, nuclear IKKα causes lung tumor progression through c-Myc, Smad2/3 and Snail activation. These results suggest that IKKα may be a promising target for intervention in human NSCLC.
“…5C). The induction of Bcl-2 expression in the H460-overexpressing IKKα cells is a marker of enhanced malignancy, as it has been found that Bcl-2 is markedly increased in lung cancer patient biopsies; additionally, its overexpression has been related with resistance against EGFR-TK inhibitors [27]. Fig.…”
Lung cancer is the leading worldwide cause of cancer mortality, however, neither curative treatments nor substantial prolonged survival has been achieved, highlighting the need for investigating new proteins responsible for its development and progression. IKKα is an essential protein for cell survival and differentiation, which expression is enhanced in human non-small cell lung cancer (NSCLC) and correlates with poor patient survival, appearing as a relevant molecule in lung cancer progression. However, there are not conclusive results about its role in this type of cancer. We have recently found that IKKα performs different functions and activates different signaling pathways depending on its nuclear or cytoplasmic localization in tumor epidermal cells. In this work, we have studied the involvement of IKKα in lung cancer progression through the generation of lung cancer cell lines expressing exogenous IKKα either in the nucleus or in the cytoplasm. We demonstrate that IKKα signaling promotes increased cell malignancy of NSCLC cells as well as lung tumor progression and metastasis in either subcellular localization, through activation of common protumoral proteins, such as Erk, p38 and mTor. But, additionally, we found that depending on its subcellular localization, IKKα has non-overlapping roles in the activation of other different pathways known for their key implication in lung cancer progression: while cytoplasmic IKKα increases EGFR and NF-κB activities in lung tumor cells, nuclear IKKα causes lung tumor progression through c-Myc, Smad2/3 and Snail activation. These results suggest that IKKα may be a promising target for intervention in human NSCLC.
“…The Bcl-2 family members are divided into apoptotic molecules, such as Bax, and anti-apoptotic molecules such as Bcl-2 and Bcl-XL. Upregulating Bcl-2 expression and imbalance expression of Bcl-2 family proteins had been confirmed to be closely related to EGFR TKIs resistance in NSCLC [36]. Several studies confirmed that after inhibiting MDM2 expression, the expression of p53 and Bax can be up-regulated, while Bcl-2 expression can be down-regulated, resulting in increased drug sensitivity in tumor cells [37, 38].…”
Section: Role Of Mdm2 and Therapeutic Resistancementioning
The MDM2 protein encoded by the mouse double minute 2 (
MDM2
) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes. Therefore, MDM2 can maintain the stability of p53 signaling pathway.
MDM2
amplification has been detected in many human malignancies, including lung cancer, colon cancer and other malignancies. MDM2 overexpression is associated with chemotherapeutic resistance in human malignancies. The mechanisms of chemotherapeutic resistance by MDM2 overexpression mainly include the p53–MDM2 loop-dependent and p53–MDM2 loop-independent pathways. But the role of MDM2 overexpression in tyrosine kinase inhibitors resistance remains to be further study. This paper reviews the possible mechanisms of therapeutic resistance of malignancies induced by
MDM2
amplification and overexpression, including chemotherapy, radiotherapy, targeted agents and hyperprogressive disease of immunotherapy. Besides, MDM2-targeted therapy may be a potential new strategy for treating advanced malignancies.
“…An inhibitor of apoptosis, survivin, causes drug resistance in cancer cells by preventing apoptosis through inactivation of caspase-9 and caspase-3 (14). Since survivin as well as anti-apoptotic members of the BCL2 family of proteins are notorious as important chemotherapeutic resistance mediators (10,21), we therefore investigated the mechanism of apoptosis induction of phoyunnanin E and its possible effects on BCL2, MCL1 and survivin.…”
Section: Phoyunnanin E Triggers Apoptosis Via P53 Activation and Suppmentioning
Background/Aim: Lung cancer is by far the most common cause of cancer mortality, accounting for nearly 20% of all global cancer deaths. Therefore, potent and effective compounds for treatment of this cancer type are essential. Phoyunnanin E, isolated from Dendrobium venustum (Orchidaceae), has promising pharmacological activities; however, it is unknown if phoyunnanin E affects apoptosis of lung cancer cells. Materials and Methods: The apoptosis-inducing activity of phoyunnanin E on H460 lung cancer cells was investigated by Hoechst 33342, and annexin V-fluorescein isothiocyanate/propidium iodide staining. The underlying mechanism was determined via monitoring apoptosis-regulatory proteins by western blot analysis. The apoptotic effect of the compound was confirmed in H23 lung cancer cells. Results: Phoyunnanin E significantly induced apoptotic cell death of H460 lung cancer cells, as indicated by condensed and fragmented nuclei with the activation of caspase-3 and-9 and poly (ADP-ribose) polymerase cleavage. Phoyunnanin E mediated apoptosis via a p53dependent pathway by increasing the accumulation of cellular p53 protein. As a consequence, anti-apoptotic proteins including induced myeloid leukemia cell differentiation protein (MCL1) and B-cell lymphoma 2 (BCL2) were found to be significantly depleted, while pro-apoptotic BCL-2-associated X protein (BAX) protein was upregulated. Furthermore, it was found that expression of an inhibitor of apoptosis, survivin, markedly reduced in response to phoyunnanin E treatment. The apoptosis-inducting effect was also found in phoyunnanin E-treated H23 lung cancer cells. Conclusion: These results indicate the promising effect of phoyunnanin E in induction of apoptosis, that may be useful for the development of novel anticancer agents. Despite intense interest in development of novel anticancer strategies, systemic chemotherapy remains the fundamental treatment of choice for lung cancer. Lung cancer is among the most common cancer types, with a very high mortality rate. The majority of all lung malignancies are non-small cell lung cancer (NSCLC). After systemic chemotherapeutic treatment, NSCLC frequently relapses, with median progression time at around 5-24 months (1). The major obstacle for successful lung cancer management is therapeutic resistance, especially in advanced-stage cancer (2), leading to the urgent need for novel, more effective drugs. Apoptosis is the main mechanism by which chemotherapeutic drugs eliminate cancer cells (3). They often induce DNA adducts or a DNA-damage signal which trigger the apoptosis pathway via the activation of p53 protein (4). It is obvious that p53 can induce apoptosis by the specific trans-activation of target genes including B-cell lymphoma 2 (BCL2)-associated X (BAX) protein (5, 6). Moreover, expression of anti-apoptotic proteins, such as myeloid leukemia cell differentiation protein (MCL1) and BCL2, are reduced by p53 activation (5-7). The induction of pro-apoptotic proteins subsequently causes pores in the mitochondrial membrane to...
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