Oncogenic role of an uncharacterized cold-induced zinc finger protein 726 in breast cancer.

The unobtrusive cold environmental temperature can be linked to the development of cancer. This study, for the first time, envisaged cold stress-mediated induction of a zinc finger protein 726 (ZNF726) in breast cancer. However, the role of ZNF726 in tumorigenesis has not been defined. This study investigated the putative role of ZNF726 in breast cancer tumorigenic potency. Gene expression analysis using multifactorial cancer databases predicted overexpression of ZNF726 in various cancers, including breast cancer. Experimental observations found that malignant breast tissues and highly aggressive MDA-MB-231 cells showed an elevated ZNF726 expression as compared to benign and luminal A type (MCF-7), respectively. Furthermore, ZNF726 silencing decreased breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion accompanied by the inhibition of colony-forming ability. Concordantly, ZNF726 overexpression significantly demonstrated opposite outcomes than ZNF726 knockdown. Taken together, our findings propose cold-inducible ZNF726 as a functional oncogene demonstrating its prominent role in facilitating breast tumorigenesis. An inverse correlation between environmental temperature and total serum cholesterol was observed in the previous study. Furthermore, experimental outcomes illustrate that cold stress elevated cholesterol content hinting at the involvement of the cholesterol regulatory pathway in cold-induced ZNF726 gene regulation. This observation was bolstered by a positive correlation between the expression of cholesterol-regulatory genes and ZNF726. Exogenous cholesterol treatment elevated ZNF726 transcript levels while knockdown of ZNF726 decreased the cholesterol content via downregulating various cholesterol regulatory gene expressions (e.g., SREBF1/2, HMGCoR, LDLR). Moreover, an underlying mechanism supporting cold-driven tumorigenesis is proposed through interdependent regulation of cholesterol regulatory pathway and cold-inducible ZNF726 expression.

Dysregulated cholesterol regulatory genes as a diagnostic biomarker for cancer.

BACKGROUND: A dysregulation of cholesterol homeostasis is often seen in various cancer cell types, and elevated cholesterol content and that of its metabolites appears to be crucial for cancer progression and metastasis. Cholesterol is a precursor of various steroid hormones and a key plasma membrane component especially in lipid-rafts, also modulating many intracellular signaling pathways. METHODS: To provide an insight of dysregulated cholesterol regulatory genes, their transcript levels were analyzed in different cancers and their influence was correlated with the overall survival of cancer patients using cancer database analysis. RESULTS: This analysis found a set of genes (e.g., ACAT1, RXRA, SOAT1 and SQLE) that were not only often dysregulated, but also had been associated with poorer overall survival in most cancer types. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed elevated SQLE and SOAT1 transcript levels and downregulated expression of RXRA and ACAT1 genes in triple negative breast cancer tissues compared to adjacent control tissues, indicating that this dysregulated expression of the gene signature is a diagnostic marker for breast cancer. CONCLUSION: For the first time, the present study identified a gene signature associated with the dysregulation of cholesterol homeostasis in cancer cells that may not only be used as a diagnostic marker, but also comprise a promising drug target for the advancement of cancer therapy.

Metformin ameliorates BMP2 induced adipocyte-like property in breast cancer cells.

Neighboring adipocytes of tumor cells/cancer associated adipocytes supply many factors and fatty acids as fuel to cancer cells for inducing cancer progression and development. Epithelial breast cancer cells also differentiate into several cell types to meet various demands. This study reports that breast cancer cells exhibit inherent adipocyte-like property which is further enhanced in presence of BMP2. Antidiabetic metformin inhibits BMP2 induced adipocyte-like potential in breast cancer cells. Interestingly, breast cancer cells not only show lipid accumulation but also have ability to release lipid content. Thus, this study centers around the presence of the adipocyte cell-like property in breast cancer cells, the significance of BMP2 and metformin that may be explored in designing therapeutics against breast cancer.

Metformin prevents osteoblast-like potential and calcification in lung cancer A549 cells.

In spite of recent advances made in understanding its progression, cancer is still a leading cause of death across the nations. Molecular pathophysiology of these cancer cells largely differs depending on cancer types and even within the same tumor. Pathological mineralization/calcification is seen in various tissues including breast, prostate, and lung cancer. Osteoblast-like cells derived after trans-differentiation of mesenchymal cells usually drive calcium deposition in various tissues. This study aims to explore the presence of osteoblast-like potential in lung cancer cells and its prevention. ALP assay, ALP staining, nodule formation, RT-PCR, RT-qPCR, and western blot analysis experiments were carried out in lung cancer A549 cells to achieve said objective. Expressions of various osteoblast markers (e.g., ALP, OPN, RUNX2, and Osterix) along with osteoinducer genes (BMP-2 and BMP-4) were observed in A549 cells. Moreover, ALP activity and ability leading to nodule formation revealed the presence of osteoblast-like potential in lung cancer cells. Here, BMP-2 treatment increased expressions of osteoblast transcription factors such as RUNX2 and Osterix, enhanced ALP activity, and augmented calcification in this cell line. It was also observed that antidiabetic metformin inhibited BMP-2 mediated increase in osteoblast-like potential and calcification in these cancer cells. The current study noted that metformin blocked BMP-2 mediated increase in epithelial to mesenchymal transition (EMT) in A549 cells. The above findings for the first time unravel that A549 cells possess osteoblast-like potential which drives lung cancer calcification. Metformin might prevent BMP-2 induced osteoblast-like phenotype of the lung cancer cells with concomitant inhibition of EMT to inhibit lung cancer tissue calcification.

Duality of bone morphogenetic proteins in cancer: A comprehensive analysis.

Over 20 different growth factors belonging to the bone morphogenetic proteins (BMPs) family have been identified, that were initially discovered as growth factors that promote osteogenesis, and play a vital role in bone remodeling and various developmental processes. Numerous studies have explored the aberrance level of BMPs in various cancer types, questioning their role in tumorigenesis. These growth factors have been studied extensively over the decades to define their function during cancer progression and metastasis. Nonetheless, the BMP expression profiles in clinical samples correlate with cancer prognosis. Based on clinical data, various in vitro, and in vivo findings, it has been reported that BMPs have dual roles, that is, they can act as a tumor suppressor, tumor promoter, and both. On contrary, some studies have reported that BMPs have an oncogenic role while others reported their tumor-suppressive role. So, this creates a knowledge gap in the behavior of different types of BMPs. Thus, this review updates and bridges the knowledge gap while considering the dual behavior of various BMPs including BMP-2, 4, 6, 7, 9, and 10. Moreover, the comprehensive analysis provides insight into the role of different BMPs in cancer potential and how the behavior of BMPs alters in the tissue-dependent context in various cancers by modulating canonical SMAD signaling, various noncanonical pathways such as PI3K/AKT, NF-κB, MAPK, STAT, cMYC, cJUN, and so forth. This review also enlightens the role of BMP heterodimers, several ligand-binding proteins (agonists and antagonists), mutational status of BMP receptors, and the tumor microenvironment in relating to the bi-functional aspects of the BMPs in various cancerous tissues by regulating the levels of BMP's canonical and noncanonical signals.

Effect of environmental factors on SARS-CoV-2 infectivity in northern hemisphere countries: a 2-year data analysis.

OBJECTIVE: The COVID-19 pandemic that emerged in December 2019 brought human life to a standstill. With over 2-year since the pandemic originated from Wuhan, SARS-CoV-2 has caused more than 6 million deaths worldwide. With the emergence of mutant strains and COVID-19 surge waves, it becomes critically important to conduct epidemiological studies that allow us to understand the role of various environmental factors on SARS-CoV-2 infectivity. Our earlier study reported a strong negative correlation between temperature and COVID-19 incidence. This research is an extension of our previous study with an attempt to understand the global analysis of COVID-19 in northern hemisphere countries. STUDY DESIGN: This research aims at achieving a better understanding of the correlation of environmental factors such as temperature, sunlight, and humidity with new cases of COVID-19 in northern hemisphere from March 2020 to February 2022. METHODS: To understand the relationship between the different environmental variants and COVID-19, a statistical approach was employed using Pearson, Spearman and Kendall analysis. RESULTS: Month-wise univariate analysis indicated a strong negative correlation of temperature and sunlight with SARS-CoV-2 infectivity, whereas inconsistencies were observed in correlation analysis in the case of humidity in winter months. Moreover, a strong negative correlation between average temperature of winter months and COVID-19 cases exists as evidenced by Pearson, Spearman, and Kendall analyses. In addition, correlation pattern between monthly temperature and COVID-19 cases of a country mimics to that of sunlight of a country. CONCLUSION: This pilot study proposes that low temperatures and low sunlight might be additional risk factors for SARS-CoV-2 infectivity, mostly in northern hemisphere countries.

N-arachidonoyl dopamine inhibits epithelial-mesenchymal transition of breast cancer cells through ERK signaling and decreasing the cellular cholesterol.

N-acyl dopamines (NADAs) are bioactive lipids of the endovanilloid family with known cytotoxicity for the cancer cells; however, the available data on the participation of the endovanilloids in epithelial-mesenchymal transition (EMT) and cancer stemness are controversial. This study unveils the inhibitory role of N-arachidonoyl dopamine (AA-DA), a typical representative of the NADA family, in breast cancer cell migration, EMT, and stemness. AA-DA treatment also led to a decrease in cholesterol biosynthesis gene expressions, and addition of exogenous cholesterol reverted these AA-DA-mediated inhibitory effects. Notably, AA-DA treatment inhibited the key regulatory gene of the cholesterol biosynthesis pathway, sterol regulatory element-binding protein 1 (SREBP1), with concurrent repression of the endoplasmic reticulum kinase 1/2 (ERK1/2) pathway. Furthermore, U0126, an ERK inhibitor, inhibited SREBP1 and decreased cellular cholesterol level, unwinding the molecular mechanism behind AA-DA-mediated anticancer activity. Thus, we, for the first time, revealed that AA-DA counteracts breast cancer EMT via inhibition of ERK signaling and cholesterol content.

Docosahexaenoic Acid (DHA) Inhibits Bone Morphogenetic Protein-2 (BMP-2) Elevated Osteoblast Potential of Metastatic Breast Cancer (MDA-MB-231) Cells in Mammary Microcalcification.

Microcalcification seems to be an assurance signature for the prediction of breast cancer malignancy. However, neither systematic study for deciphering the molecular mechanism of mammary microcalcification has yet been conducted, nor a mechanistic study has been performed to find out its prevention. Thus, this study firstly aimed at determining if malignant breast tissues/metastatic breast cancer cells exhibit elevated intrinsic osteoblast-like potential responsible for driving the pathological microcalcification in breast tumors. Here, tumor sample analysis showed higher levels of various osteogenic genes (e.g., Runx2, osterix), and increased ALP activity and calcification in malignant breast tissues when compared to benign tissues, indicating the existence of elevated osteoblast-like potential in malignant breast tissues as compared to benign tissues. Similarly, cell culture study found that metastatic MDA-MB-231 cells acquired a higher osteoblast-like potential as compared to less metastatic breast cancer MCF-7 cells. It was also noticed that osteoinducer bone morphogenetic protein 2 (BMP-2) increased osteoblast-like differentiation and calcification potential in breast cancer cells. Moreover, omega-3 fatty acid docosahexaenoic acid (DHA) showed an inhibitory effect on BMP-2 induced osteoblast-like potential presumably by abrogating BMP signaling. Thus, this study for the first time unraveled that DHA may mitigate microcalcification by blocking osteoblast-like potential of breast cancer cells.

Can the summer temperatures reduce COVID-19 cases?

OBJECTIVE: Despite huge global, national, and local preventive measures including travel restriction, social distancing, and quarantines, the outbreak of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develops the coronavirus disease 2019 (COVID-19) worldwide pandemic. SARS-CoV-2 emerging from Wuhan, China, took only three months to cover >200 countries worldwide by infecting more than 2.4 million people and killing more than 150,000 people. Although this infection at the early stage creates seasonal flu-like symptoms with a higher illness, it eventually causes a higher mortality. Epidemiological studies not only find the causes of many health issues but also suggest preventive measures. This study aimed to see the link between environment temperature and COVID-19 cases. STUDY DESIGN: The monthly average environment temperature (MAET) and various COVID-19 cases of a country were collected and analyzed to see the relationship between these parameters. METHODS: Univariate analysis and statistical modeling were used to determine the relationship between environment temperature and different COVID-19 cases. RESULTS: This study found that the majorities of the countries having higher COVID-19 cases are located in the higher latitude (colder region) in the globe. As of 20th April data available, statistical analyses by various methods have found that strong negative correlations with statistical significance exist between MAET and several COVID-19 cases including total cases, active cases, and cases per million of a country (Spearman correlation coefficients were -0.45, -0.42, and -0.50 for total cases, active cases, and cases/per million, respectively). Analysis by the statistical log-linear regression model further supports that the chance of patients to contract COVID-19 is less in warmer countries than in colder countries. CONCLUSION: This pilot study proposes that cold environment may be an additional risk factor for COVID-19 cases.

Cold-hearted: A case for cold stress in cancer risk.

A negative correlation exists between environmental temperature and cancer risk based on both epidemiological and statistical analyses. Previously, cold stress was reported to be an effective cause of tumorigenesis. Several studies have demonstrated that cold temperature serves as a potential risk factor in cancer development. Most recently, a link was demonstrated between the effects of extreme cold climate on cancer incidence, pinpointing its impact on tumour suppressor genes by causing mutation. The underlying mechanism behind cold stress and its association with tumorigenesis is not well understood. Hence, this review intends to shed light on the role of associated factors, genetic and/or non-genetic, which are modulated by cold temperature, and eventually influence tumorigenic potential. While scrutinizing the effect of cold exposure on the body, the expression of certain genes, e.g. uncoupled proteins and heat-shock proteins, were elevated. Biological chemicals such as norepinephrine, thyroxine, and cholesterol were also elevated. Brown adipose tissue, which plays an essential role in thermogenesis, displayed enhanced activity upon cold exposure. Adaptive measures are utilized by the body to tolerate the cold, and in doing so, invites both epigenetic and genetic changes. Unknowingly, these adaptive strategies give rise to a lethal outcome i.e., genesis of cancer. Concisely, this review attempts to draw a link between cold stress, genetic and epigenetic changes, and tumorigenesis and aspires to ascertain the mechanism behind cold temperature-mediated cancer risk.

Can the aging influence cold environment mediated cancer risk in the USA female population?

Cancer is one of the most debilitating diseases worldwide. Cancer incidence and/or death depends on several intrinsic and extrinsic factors (e.g., dietary habits, socio-behavioral activities, physical inactivity, smoking, alcohol consumption, gender, races/ethnicities and age). Various studies have found that an inverse relationship subsists between environmental temperature and cancer risk. Furthermore, this negative relationship was found to be more consistent in the USA female population. This research mainly focuses on influence of aging on cold environment mediated cancer risk for overall and various anatomical site-specific cancers. Age-specific county-wise data of cancer incidence rate (CIR) in the USA female population was selected in this study. Statistical analysis found a negative correlation between the average annual temperature (AAT) and CIR in all anatomical sites (AAS; overall) as well as different anatomical site-specific cancers (e.g., breast, melanoma, leukaemia, pancreas, bladder, uterus, thyroid and non-Hodgkin's lymphoma (NHL), except for cervical cancer) in different age groups (e.g., less than 50 years, 50 plus years, less than 65 years and 65 plus years). In addition, an inverse relationship between the AAT and CIR was found in case of paediatric cancer. However, all the results obtained from the linear model based statistical analysis proposed that the older age-group of females particularly above 65 years seems to be more prone to cold temperature linked cancer risk. For example, age-specific cold linked cancer incidence appears to be more inclined in case of breast cancer in the age-group of 65 plus years. This study, for first time, proposes that aging may have a positive influence on the relationship between cancer incidence and environment temperature.

Bone Morphogenetic Protein-2 (BMP-2) Activates NFATc1 Transcription Factor via an Autoregulatory Loop Involving Smad/Akt/Ca2+ Signaling.

Bone remodeling is controlled by dual actions of osteoclasts (OCs) and osteoblasts (OBs). The calcium-sensitive nuclear factor of activated T cells (NFAT) c1 transcription factor, as an OC signature gene, regulates differentiation of OCs downstream of bone morphogenetic protein-2 (BMP-2)-stimulated osteoblast-coded factors. To analyze a functional link between BMP-2 and NFATc1, we analyzed bones from OB-specific BMP-2 knock-out mice for NFATc1 expression by immunohistochemical staining and found significant reduction in NFATc1 expression. This indicated a requirement of BMP-2 for NFATc1 expression in OBs. We showed that BMP-2, via the receptor-specific Smad pathway, regulates expression of NFATc1 in OBs. Phosphatidylinositol 3-kinase/Akt signaling acting downstream of BMP-2 also drives NFATc1 expression and transcriptional activation. Under the basal condition, NFATc1 is phosphorylated. Activation of NFAT requires dephosphorylation by the calcium-dependent serine/threonine phosphatase calcineurin. We examined the role of calcium in BMP-2-stimulated regulation of NFATc1 in osteoblasts. 1,2Bis(2aminophenoxy)ethaneN,N,N',N'-tetraacetic acid acetoxymethyl ester, an inhibitor of intracellular calcium abundance, blocked BMP-2-induced transcription of NFATc1. Interestingly, BMP-2 induced calcium release from intracellular stores and increased calcineurin phosphatase activity, resulting in NFATc1 nuclear translocation. Cyclosporin A, which inhibits calcineurin upstream of NFATc1, blocked BMP-2-induced NFATc1 mRNA and protein expression. Expression of NFATc1 directly increased its transcription and VIVIT peptide, an inhibitor of NFATc1, suppressed BMP-2-stimulated NFATc1 transcription, confirming its autoregulation. Together, these data show a role of NFATc1 downstream of BMP-2 in mouse bone development and provide novel evidence for the presence of a cross-talk among Smad, phosphatidylinositol 3-kinase/Akt, and Ca(2+) signaling for BMP-2-induced NFATc1 expression through an autoregulatory loop.

Colder environments are associated with a greater cancer incidence in the female population of the United States.

Cancer incidence and/or mortality among individuals varies with diet, socio-culture, ethnicity, race, gender, and age. Similarly, environmental temperature modulates many biological functions. To study the effect of environment temperature on cancer incidence, the US population was selected. Because, county-wise cancer incidence rate data of various anatomical site-specific cancers and different races/ethnicities for both males and females are available. Moreover, the differences amongst the aforementioned factors among individuals are much less, as compared to the world population. Statistical analysis showed a negative correlation between the average annual temperature and cancer incidence rate at all anatomical sites and individually for 13 types (out of 16 types) of anatomical site-specific cancer incidence rates (e.g. uterine, bladder, thyroid, breast, esophagus, ovary, melanoma, non-Hodgkin lymphoma, leukemia, brain, pancreas, etc.) for females. Further analysis found a similar inverse trend in all races/ethnicities of the female population but not in all male races/ethnicities or anatomical site-specific cancers. Moreover, the majority of the counties having the top-most cancer incidence rate in females are located above the latitude 36.5°N. These findings indicate that living in a cold county in the United States might have a higher risk of cancer irrespective of cancer type (except cervical and liver) and races/ethnicities for females but not in all such cases for the male population.

Simvastatin and MBCD Inhibit Breast Cancer-Induced Osteoclast Activity by Targeting Osteoclastogenic Factors.

Previous reports have documented that cholesterol-lowering simvastatin prevented osteolytic metastasis of breast cancer in animal model in which cancer cells were placed into blood circulation. Thus, simvastatin treatment might have a preventive effect in inhibiting osteoclast activity of metastatic bone microenvironment. This study documented that both simvastatin and MBCD (cholesterol depleting drug) blocked the breast cancer-induced TRAP and MMP activity, and expressions of various osteoclastogenic genes (TRAP, Cathepsin K, and NFATc1) in pre-osteoclast RAW264.7 cells, and osteoclastogenic CSF-1 and RANKL expressions in breast cancer MCF-7 cells. Thus, these findings unravel a molecular mechanism of simvastatin-/MBCD-mediated inhibition of breast cancer-driven osteoclast activity.

A Molecular View of Pathological Microcalcification in Breast Cancer.

Breast microcalcification is a potential diagnostic indicator for non-palpable breast cancers. Microcalcification type I (calcium oxalate) is restricted to benign tissue, whereas type II (calcium hydroxyapatite) occurs both in benign as well as in malignant lesions. Microcalcification is a pathological complication of the mammary gland. Over the past few decades, much attention has been paid to exploit this property, which forms the basis for advances in diagnostic procedures and imaging techniques. The mechanism of its formation is still poorly understood. Hence, in this paper, we have attempted to address the molecular mechanism of microcalcification in breast cancer. The central theme of this communication is "how a subpopulation of heterogeneous breast tumor cells attains an osteoblast-like phenotype, and what activities drive the process of pathophysiological microcalcification, especially at the invasive or infiltrating front of breast tumors". The role of bone morphogenetic proteins (BMPs) and tumor associated macrophages (TAMs) along with epithelial to mesenchymal transition (EMT) in manipulating this pathological process has been highlighted. Therefore, this review offers a novel insight into the mechanism underlying the development of microcalcification in breast carcinomas.

Is cholesterol a mediator of cold-induced cancer?

Many factors such as smoking, obesity, and high fat have been either directly or indirectly linked to cancer deaths and/or incidences. Similarly, abnormal serum cholesterol levels have been assigned as a risk factor for cancer, but some studies show a discrepant result. To resolve this discrepancy, we have analyzed cholesterol data of 166 countries. Univariate analysis showed a positive correlation between serum average total cholesterol (ATC) and overall cancer mortality rate (CMR) [tau = 0.277, z = 5.19, p < 0.0001]. It was also observed that a similar positive correlation was found between ATC and different anatomical site-specific CMRs in lung, bladder, ovarian, breast, and pancreatic cancers. Our recent published data documented an existence of a negative correlation between average annual temperature (AAT) and overall CMR, as well as CMR of the abovementioned anatomical site-specific cancers. Statistical analysis further shows a negative correlation between AAT and ATC, similar to that of AAT and CMR. The resulting patterns of univariate analysis between AAT and CMR are almost identical with AAT and ATC, when this analysis was performed every 2 °C of AAT increment for all countries. Moreover, geographical location of the top 50 countries having the highest CMR is almost similar to the top 50 countries having the highest ATC. Similarly, the least 50 countries having the lowest CMR are located in the same geographical region, similar to the least 50 countries having the lowest ATC. These data along with other literature reports suggest that cholesterol could be a mediator of cold-induced cancer mortality.

A link between cold environment and cancer.

Many risk factors such as smoking and change of life style have been shown to promote genetic and adaptive epigenetic changes responsible for tumorigenesis. This study brings environmental temperature as a cancer causing factor to light. The cancer mortality rate (CMR) of a country was correlated with 17 different variables. Multivariate analysis of a total of 188 countries found that the average annual temperature (AAT) of a country might have a significant contribution to cancer death when compared with other factors such as alcohol and meat consumption. Univariate analysis found a negative correlation between AAT and CMR. All these countries were categorized into three temperature zones (zone I, -2 to 11.5 °C; number of countries, 38; zone II, 11.6 to 18.6 °C; number of countries, 32; and zone III, 18.7 to 30 °C; number of countries, 118). Out of the top-most 50 countries having the highest CMR, 26 (68.42 %), 10 (31.25 %), and 14 (11.66 %) belong to zone I, zone II, and zone III, respectively. Out of the least 50 countries having the lowest CMR, 1 (2.63 %), 4 (12.5 %), and 45 (37.5 %) belong to zone I, zone II, and zone III, respectively. CMR is low in those countries situated near to the Torrid zone (33(°) N to 23.5(°)S), but it is high for those countries situated away from these two latitudes. These data indicate that cold temperature may have a contribution in increasing tumorigenesis. High metabolic stress, which is the result of maintaining our body temperature against a cold environment, could be the possible cause for the higher cancer mortality.

miR-214: a potential biomarker and therapeutic for different cancers.

miRNAs (miRs), or small approximately 22-nucleotide-long single-stranded noncoding RNA molecules, interact with 3' untranslated regions of target mRNAs, leading to inhibition of protein production. miR-214 is often dysregulated in various cancers, which governs both tumorigenic and tumor suppressive functions. This review focuses on the current knowledge of miR-214 switching in diverse forms of cancer either by its upregulation or downregulation and sheds light on the mechanism of its tumorigenic and suppressive roles. This article describes known targets and signaling pathways that impact tumorigenesis and tumor suppression and summarizes all information available on circulating levels of miR-214 to address whether miR-214 may function as a potential biomarker and therapy for cancer patients in the future.

c-Abl-dependent molecular circuitry involving Smad5 and phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2-induced osteogenesis.

Skeletal remodeling consists of timely formation and resorption of bone by osteoblasts and osteoclasts in a quantitative manner. Patients with chronic myeloid leukemia receiving inhibitors of c-Abl tyrosine kinase often show reduced bone remodeling due to impaired osteoblast and osteoclast function. BMP-2 plays a significant role in bone generation and resorption by contributing to the formation of mature osteoblasts and osteoclasts. The effects of c-Abl on BMP-2-induced bone remodeling and the underlying mechanisms are not well studied. Using a pharmacological inhibitor and expression of a dominant negative mutant of c-Abl, we show an essential role of this tyrosine kinase in the development of bone nodules containing mature osteoblasts and formation of multinucleated osteoclasts in response to BMP-2. Calvarial osteoblasts prepared from c-Abl null mice showed the absolute requirement of this tyrosine kinase in maturation of osteoblasts and osteoclasts. Activation of phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling by BMP-2 leads to osteoblast differentiation. Remarkably, inhibition of c-Abl significantly suppressed BMP-2-stimulated PI 3-kinase activity and its downstream Akt phosphorylation. Interestingly, c-Abl regulated BMP-2-induced osteoclastogenic CSF-1 expression. More importantly, we identified the requirements of c-Abl in BMP-2 autoregulation and the expressions of alkaline phosphatase and osterix that are necessary for osteoblast differentiation. c-Abl contributed to BMP receptor-specific Smad-dependent transcription of CSF-1, osterix, and BMP-2. Finally, c-Abl associates with BMP receptor IA and regulates phosphorylation of Smad in response to BMP-2. We propose that activation of c-Abl is an important step, which induces into two signaling pathways involving noncanonical PI 3-kinase and canonical Smads to integrate BMP-2-induced osteogenesis.

A Perspective on Bone Morphogenetic Proteins: Dilemma behind Cancer- related Responses.

Bone morphogenetic proteins are a center of serious concern and are known to execute various cancer-related issues. The BMP signaling cascades have become more unpredictable as a result of their pleiotropic and risky characteristics, particularly when it comes to cancer responses. This perspective discusses the current therapeutic implications, emphasizes different cellular aspects that impact the failures of the current drug treatments, and speculates on future research avenues that include novel strategies like metabolomic studies and bio-mimetic peptide therapeutics to mitigate cancerous outcomes.