scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

scholarly journals HER2 missense mutations have distinct effects on oncogenic signaling and migration

2015 ◽  
Vol 112 (45) ◽  
pp. E6205-E6214 ◽  
Author(s):  
Daniel J. Zabransky ◽  
Christopher L. Yankaskas ◽  
Rory L. Cochran ◽  
Hong Yuen Wong ◽  
Sarah Croessmann ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
And Migration ◽  
Endogenous Loci

Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.

Clinical, Cellular, and Molecular Aspects of Cancer Invasion

2003 ◽  
Vol 83 (2) ◽  
pp. 337-376 ◽  
Author(s):  
Marc Mareel ◽  
Ancy Leroy
Keyword(s):  
Cancer Cells ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Platelet Activating Factor ◽  
Tumor Development ◽  
Genetic Alterations ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Host Cells

Invasion causes cancer malignancy. We review recent data about cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis, and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancer-related cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival, migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin, trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive fragments from cell surface glycoproteins.

scholarly journals Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization

2021 ◽  
Author(s):  
Veronica Mendoza-Reinoso ◽  
Patricia M Schnepp ◽  
Dah Youn Baek ◽  
John R Rubin ◽  
Ernestina Schipani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Cytokine Gene Expression ◽  
Prostate Cancer Cells ◽  
Significant Enrichment ◽  
Hif Prolyl Hydroxylase ◽  
Phosphorylated Stat3 ◽  
Pro Inflammatory Cytokines

Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1α stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1α-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by tumor-associated macrophages triggers p-STAT3/HIF-1α/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.

scholarly journals ID:2037 Molecular mechanisms underlying resistance to MEK1/2 inhibitor in BRAF-mutated colorectal cancer

2017 ◽  
Vol 4 (S) ◽  
pp. 68
Author(s):  
Hong-Quan Duong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Scaffold Protein ◽  
Colorectal Carcinomas ◽  
Intrinsic Resistance ◽  
Oncogenic Signaling ◽  
Colorectal Cancer Cells

Colorectal carcinomas are characterized by multiple genetic alterations, including constitutive Wnt activity and gain-of-function mutations in K-RAS and B-RAF. BRAF encodes a Ser/Thr kinase acting in the Ras/MEK/ERK pathway and the V600E mutation found in 11% of colorectal cancers renders this kinase constitutively active. B-RAF mutated colorectal carcinomas represents a very aggressive entity with a poor prognosis. Understanding the molecular mechanisms activated downstream of mutated B-RAF is urgently needed to design new therapeutic avenues to treat B-ARF mutated colorectal carcinomas and to circumvent resistance to therapies targeting the Ras/Raf/MEK1/ERK1/2 pathway. In a search for candidates that critically contribute to both intrinsic and acquired resistance to MEK1 inhibition in B-RAF mutated colorectal cancer cells, we identified one scaffold protein whose expression is driven by both NF-kB and AP-1 families of transcription factors. This scaffold protein promotes the expression of HER2 and HER3 in colorectal cancer cells subjected to MEK1 or B-RAF inhibition (Selumetinib and Vemurafenib, respectively) and, as such, is critically involved in the intrinsic resistance to these targeted therapies. The same scaffold protein is also strongly induced in B-RAF but not K-RAS mutated colorectal cancer cells showing acquired resistance to MEK1 inhibition. Interfering with the expression of this scaffold protein circumvents both intrinsic and acquired resistance to Selumetinib in B-RAF mutated colorectal cancer cells. Our study defines a new molecular actor critically involved in oncogenic signaling pathways triggered by mutated B-RAF. Our study also defineS new combinatory therapies to better treat B-RAF-mutated colorectal carcinomas.

scholarly journals Regulatory MicroRNAs in T2DM and Breast Cancer

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 819
Author(s):  
Ilhaam Ayaz Durrani ◽  
Attya Bhatti ◽  
Peter John
Keyword(s):  
Breast Cancer ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Tumorigenic Potential ◽  
Cancer Types

MicroRNAs orchestrate the tight regulation of numerous cellular processes and the deregulation in their activities has been implicated in many diseases, including diabetes and cancer. There is an increasing amount of epidemiological evidence associating diabetes, particularly type 2 diabetes mellitus, to an elevated risk of various cancer types, including breast cancer. However, little is yet known about the underlying molecular mechanisms and even less about the role miRNAs play in driving the tumorigenic potential of the cell signaling underlying diabetes pathogenesis. This article reviews the role of miRNA in bridging the diabetes–breast cancer association by discussing specific miRNAs that are implicated in diabetes and breast cancer and highlighting the overlap between the disease-specific regulatory miRNA networks to identify a 20-miRNA signature that is common to both diseases. Potential therapeutic targeting of these molecular players may help to alleviate the socioeconomic burden on public health that is imposed by the type 2 diabetes mellitus (T2DM)–breast cancer association.

scholarly journals Molecular mechanisms of cancer metastasis via the lymphatic versus the blood vessels

2021 ◽  
Author(s):  
Stanley P. Leong ◽  
Kamila Naxerova ◽  
Laura Keller ◽  
Klaus Pantel ◽  
Marlys Witte
Keyword(s):  
Lymph Node ◽  
Cancer Cells ◽  
Blood Vessels ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Distant Metastases ◽  
Nodal Basin ◽  
Cancer Types

AbstractCancer metastasis is the process by which primary cancer cells invade through the lymphatic or blood vessels to distant sites. The molecular mechanisms by which cancer cells spread either through the lymphatic versus blood vessels or both are not well established. Two major developments have helped us to understand the process more clearly. First, the development of the sentinel lymph node (SLN) concept which is well established in melanoma and breast cancer. The SLN is the first lymph node in the draining nodal basin to receive cancer cells. Patients with a negative SLN biopsy show a significantly lower incidence of distant metastasis, suggesting that the SLN may be the major gateway for cancer metastasis in these cancer types. Second, the discovery and characterization of several biomarkers including VEGF-C, LYVE-1, Podoplanin and Prox-1 have opened new vistas in the understanding of the induction of lymphangiogenesis by cancer cells. Cancer cells must complete multiple steps to invade the lymphatic system, some of which may be enabled by the evolution of new traits during cancer progression. Thus, cancer cells may spread initially through the main gateway of the SLN, from which evolving cancer clones can invade the blood vessels to distant sites. Cancer cells may also enter the blood vessels directly, bypassing the SLN to establish distant metastases. Future studies need to pinpoint the molecules that are used by cancer cells at different stages of metastasis via different routes so that specific therapies can be targeted against these molecules, with the goal of stopping or preventing cancer metastasis.

scholarly journals Computational Approaches to Prioritize Cancer Driver Missense Mutations

2018 ◽  
Vol 19 (7) ◽  
pp. 2113 ◽  
Author(s):  
Feiyang Zhao ◽  
Lei Zheng ◽  
Alexander Goncearenco ◽  
Anna Panchenko ◽  
Minghui Li
Keyword(s):  
Cancer Progression ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Rapid Development ◽  
Genomic Data ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Missense Mutations ◽  
Computational Approaches

Cancer is a complex disease that is driven by genetic alterations. There has been a rapid development of genome-wide techniques during the last decade along with a significant lowering of the cost of gene sequencing, which has generated widely available cancer genomic data. However, the interpretation of genomic data and the prediction of the association of genetic variations with cancer and disease phenotypes still requires significant improvement. Missense mutations, which can render proteins non-functional and provide a selective growth advantage to cancer cells, are frequently detected in cancer. Effects caused by missense mutations can be pinpointed by in silico modeling, which makes it more feasible to find a treatment and reverse the effect. Specific human phenotypes are largely determined by stability, activity, and interactions between proteins and other biomolecules that work together to execute specific cellular functions. Therefore, analysis of missense mutations’ effects on proteins and their complexes would provide important clues for identifying functionally important missense mutations, understanding the molecular mechanisms of cancer progression and facilitating treatment and prevention. Herein, we summarize the major computational approaches and tools that provide not only the classification of missense mutations as cancer drivers or passengers but also the molecular mechanisms induced by driver mutations. This review focuses on the discussion of annotation and prediction methods based on structural and biophysical data, analysis of somatic cancer missense mutations in 3D structures of proteins and their complexes, predictions of the effects of missense mutations on protein stability, protein-protein and protein-nucleic acid interactions, and assessment of conformational changes in protein conformations induced by mutations.

scholarly journals A Ruthenium(II) N-Heterocyclic Carbene (NHC) Complex with Naphthalimide Ligand Triggers Apoptosis in Colorectal Cancer Cells via Activating the ROS-p38 MAPK Pathway

2018 ◽  
Vol 19 (12) ◽  
pp. 3964 ◽  
Author(s):  
Yasamin Dabiri ◽  
Alice Schmid ◽  
Jannick Theobald ◽  
Biljana Blagojevic ◽  
Wojciech Streciwilk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
P38 Mapk Pathway ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
Cellular Reactive Oxygen Species ◽  
Cancer Types ◽  
Apoptotic Effects

The p38 MAPK pathway is known to influence the anti-tumor effects of several chemotherapeutics, including that of organometallic drugs. Previous studies have demonstrated the important role of p38 both as a regulator and a sensor of cellular reactive oxygen species (ROS) levels. Investigating the anti-cancer properties of novel 1,8-naphthalimide derivatives containing Rh(I) and Ru(II) N-heterocyclic carbene (NHC) ligands, we observed a profound induction of ROS by the complexes, which is most likely generated from mitochondria (mtROS). Further analyses revealed a rapid and consistent activation of p38 signaling by the naphthalimide-NHC conjugates, with the Ru(II) analogue—termed MC6—showing the strongest effect. In view of this, genetic as well as pharmacological inhibition of p38α, attenuated the anti-proliferative and pro-apoptotic effects of MC6 in HCT116 colon cancer cells, highlighting the involvement of this signaling molecule in the compound’s toxicity. Furthermore, the influence of MC6 on p38 signaling appeared to be dependent on ROS levels as treatment with general- and mitochondria-targeted anti-oxidants abrogated p38 activation in response to MC6 as well as the molecule’s cytotoxic- and apoptogenic response in HCT116 cells. Altogether, our results provide new insight into the molecular mechanisms of naphthalimide-metal NHC analogues via the ROS-induced activation of p38 MAPK, which may have therapeutic interest for the treatment of various cancer types.

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