The mitogen-activated protein kinases(MAPK) pathway, often known as the RAS-RAFMEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell ...The mitogen-activated protein kinases(MAPK) pathway, often known as the RAS-RAFMEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.展开更多
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding ...Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.展开更多
microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indica...microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development, miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer-related inflam- mation, anti-cancer drug resistance, and regulation of cancer stem ceils. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.展开更多
The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream...The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.展开更多
Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to th...Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.展开更多
文摘The mitogen-activated protein kinases(MAPK) pathway, often known as the RAS-RAFMEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.
文摘Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
基金supported by National Natural Science Foundation of China grants (No. 30872889, 81072215, 81001210, 81172580)Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 20098-8-2)+1 种基金State Key Laboratory of Oral Diseases Open Funding (SKLODOF2010-05)the Fundamental Research Funds of the Central Universities of China (2011)
文摘microRNAs （miRNAs） are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Studies have shown that thousands of human protein-coding genes are regulated by miRNAs, indicating that miRNAs are master regulators of many important biological processes, such as cancer development, miRNAs frequently have deregulated expression in many types of human cancers, and play critical roles in tumorigenesis, which functions either as tumor suppressors or as oncogenes. Recent studies have shown that miRNAs are highly related with cancer progression, including initiating, growth, apoptosis, invasion, and metastasis. Furthermore, miRNAs are shown to be responsible for the cancer-related inflam- mation, anti-cancer drug resistance, and regulation of cancer stem ceils. Therefore, miRNAs have generated great interest as a novel strategy in cancer diagnosis and therapy. Here we review the versatile roles of miRNAs in cancers and their potential applications for diagnosis, prognosis, and treatment as biomarkers.
文摘The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.
基金Supported by a Grant from the Italian Liver Foundation
文摘Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.
