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The increased propensity of BRCA1 mutation carriers to develop aggressive breast tumors with stemlike properties begins to be understood in terms of osteoprotegerin (OPG)-unrestricted cross-talk between RANKL-overproducing progesterone-sensor cells and cancer-initiating RANK C responder cells that reside within pre-malignant BRCA1 mut/C breast epithelial tissue. We recently proposed that, in the absence of hormone influence, cancer-initiating cells might remain responsive to RANKL stimulation,doi:10.1080/15384101.2017.1310353 pmid:28387573 pmcid:PMC5499830 fatcat:b5vbondpnjg2djrzmsoj5b5zxq
more »... nd hence to the therapeutic effects of the anti-RANKL antibody denosumab because genomic instability induced by BRCA1 haploinsufficiency might suffice to cell-autonomously hyperactivate RANKL gene expression. Here we report that the biguanide metformin prevents BRCA1 haploinsufficiency-driven RANKL gene overexpression, thereby disrupting an auto-regulatory feedback control of RANKL-addicted cancer stem cell-like states within BRCA1 mut/¡ cell populations. Moreover, metformin treatment elicits a synergistic decline in the breast cancer-initiating cell population and its self-renewal capacity in BRCA1-mutated basal-like breast cancer cells with bone metastasis-initiation capacity that exhibit primary resistance to denosumab in mammosphere assays. The specific targeting of RANKL/RANK signaling with denosumab is expected to revolutionize prevention and treatment strategies currently available for BRCA1 mutation carriers. Our findings provide a rationale for new denosumab/metformin combinatorial strategies to clinically manage RANKL-related breast oncogenesis and metastatic progression. haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells. Oncotarget 2017; [epub ahead of print]; PMID:28388533; https://doi.
Conflicts of Interest: Joaquim Bosch-Barrera reports grants and personal fees from Roche-Genentech, grants from Pfizer and Pierre Fabre, and personal fees from MSD, BMS, AstraZeneca, Boehringer-Ingelheim ...doi:10.3390/ph14060559 pmid:34208282 pmcid:PMC8230811 fatcat:6bpxnu2mjbgkrlhxr7ibyfnrba
Joaquim Bosch-Barrera is the recipient of research grants from La Marató de TV3 foundation (201906) and the Health Research and Innovation Strategic Plan (SLT006/17/114; PERIS 2016-2020; Pla stratègic ...doi:10.3390/cancers12071757 pmid:32630618 fatcat:sxbzjxzidvfybakcbpbjwrdtq4
The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactordoi:10.3390/nu11071656 pmid:31331073 pmcid:PMC6683035 fatcat:o44jbp3u3vcljbhi7dcwzvvcwe
more »... avin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC50 as low as 2.5 μmol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.
Note: A detailed description of this procedure is given in: Marta Riera-Borrull, Esther Rodríguez-Gallego, Anna Hernández-Aguilera, Rosa Ras, Elisabet Cuyàs, Jordi Camps, Angel G, Corbí, Antonio Segura-Carretero ...doi:10.18632/oncotarget.3733 pmid:25980580 pmcid:PMC4494938 fatcat:kloozrml2jgotokaul7twsy32m
Personalized cancer medicine based on the analysis of tumors en masse is limited by tumor heterogeneity, which has become a major obstacle to effective cancer treatment. Cancer stem cells (CSC) are emerging as key drivers of interand intratumoral heterogeneity. CSC have unique metabolic dependencies that are required not only for specific bioenergetic/biosynthetic demands but also for sustaining their operational epigenetic traits, i.e. self-renewal, tumor-initiation, and plasticity. Given thatdoi:10.18632/oncotarget.21834 pmid:29245896 pmcid:PMC5725087 fatcat:mdomfyyz5fhnbdpyghmfh5iwrm
more »... the metabolome is the final downstream product of all the -omic layers and, therefore, most representative of the biological phenotype, we here propose that a novel approach to better understand the complexity of tumor heterogeneity is by mapping and cataloging small numbers of CSC metabolomic phenotypes. The narrower metabolomic diversity of CSC states could be employed to reduce multidimensional tumor heterogeneity into dynamic models of fewer actionable sub-phenotypes. The identification of the driver nodes that are used differentially by CSC states to metabolically regulate self-renewal and tumor initation and escape chemotherapy might open new preventive and therapeutic avenues. The mapping of CSC metabolomic states could become a pioneering strategy to reduce the dimensionality of tumor heterogeneity and improve our ability to examine changes in tumor cell populations for cancer detection, prognosis, prediction/monitoring of therapy response, and detection of therapy resistance and recurrent disease. The identification of driver metabolites and metabolic nodes accounting for a large amount of variance within the CSC metabolomic sub-phenotypes might offer new unforeseen opportunities for reducing and exploiting tumor heterogeneity via metabolic targeting of CSC.
Patients with wild-type KRAS metastatic colorectal cancer (mCRC) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies. Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR-directed antibody cetuximab. Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab, we uncovered an unexpected mechanism ofdoi:10.3892/or.2017.5682 pmid:28560458 fatcat:dcjbrzdqivcgdd4d6p6vwp6dbu
more »... tance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis. Parental NRAS +/+ cells, but not NRAS Q61K/+ cells, activated the ephrin receptor ephA1 in response to cetuximab treatment. Moreover, whereas cetuximab treatment significantly downregulated EPHA2 gene expression in NRAS +/+ cells, EPHA2 expression in NRAS Q61K/+ cells was refractory to cetuximab. Remarkably, pharmacologically mimicked ephrin-A1 engagement to ephA2 converted NRAS-mutant into RAS wild-type mCRC cells in terms of cetuximab efficacy. Accordingly, activation of the ephA2 receptor by bioactive recombinant human ephrin-A1/Fc-fusion protein suppressed the cetuximab-unresponsive hyperactivation of MAPK and AKT and fully restored cetuximab activity in NRAS-mutant colorectal cells. Collectively, these findings reveal that the clinical benefit of cetuximab in mCRC might necessarily involve the suppression of the ligandless oncogenic signaling of the ephA2 receptor. Hence, ligand-dependent tumor suppressor signaling using therapeutic ephA2 agonists might offer new therapeutic opportunities to clinically widen the use of cetuximab in NRAS-mutated and/or ephA2-dependent mCRC tumors.
The signal transducer and activator of transcription 3 (STAT3) has been suggested to play a prominent role in mediating non-small-cell lung cancer (NSCLC) resistance to some tyrosine kinase inhibitor (TKI)mediated therapies. Using a model of anaplastic lymphoma kinase gene (ALK)-translocated NSCLC with acquired resistance to the ALK TKI crizotinib, but lacking amplifications or mutations in the kinase domain of ALK, we herein present evidence that STAT3 activation is a novel mechanism ofdoi:10.1080/15384101.2016.1245249 pmid:27753543 pmcid:PMC5224449 fatcat:ig3rmrzjsfegroftuassgj265e
more »... nib resistance that involves the upregulation of immune escape and epithelial to mesenchymal transition (EMT) signaling pathways. Taking advantage of the flavonolignan silibinin as a naturally occurring STAT3targeted pharmacological inhibitor, we confirmed that STAT3 activation protects ALK-translocated NSCLC from crizotinib. Accordingly, silibinin-induced inhibition of STAT3 worked synergistically with crizotinib to reverse acquired resistance and restore sensitivity in crizotinib-resistant cells. Moreover, silibinin treatment significantly inhibited the upregulation of the immune checkpoint regulator PD-L1 and also EMT regulators (e.g., SLUG, VIM, CD44) in crizotinib-refractory cells. These findings provide a valuable strategy to potentially improve the efficacy of ALK inhibition by cotreatment with silibinin-based therapeutics, which merit clinical investigation for ALK TKI-resistant NSCLC patients.
Cancer stem cells (CSC) may take advantage of the Warburg effect-induced siphoning of metabolic intermediates into de novo fatty acid biosynthesis to increase self-renewal growth. We examined the anti-CSC effects of the antifungal polyketide soraphen A, a specific inhibitor of the first committed step of lipid biosynthesis catalyzed by acetyl-CoA carboxylase (ACACA). The mammosphere formation capability of MCF-7 cells was reduced following treatment with soraphen A in a dose-dependent manner.doi:10.18632/oncotarget.2059 pmid:25246709 pmcid:PMC4226684 fatcat:lxblar23wrc3zmsn2lj3drebku
more »... F-7 cells engineered to overexpress the oncogene HER2 (MCF-7/HER2 cells) were 5-fold more sensitive than MCF-7 parental cells to soraphen A-induced reductions in mammosphere-forming efficiency. Soraphen A treatment notably decreased aldehyde dehydrogenase (ALDH)-positive CSC-like cells and impeded the HER2's ability to increase the ALDH + -stem cell population. The following results confirmed that soraphen A-induced suppression of CSC populations occurred through ACACA-driven lipogenesis: a.) exogenous supplementation with supraphysiological concentrations of oleic acid fully rescued mammosphere formation in the presence of soraphen A and b.) mammosphere cultures of MCF-7 cells with stably silenced expression of the cytosolic isoform ACACA1, which specifically participates in de novo lipogenesis, were mostly refractory to soraphen A treatment. Our findings reveal for the first time that ACACA may constitute a previously unrecognized target for novel anti-breast CSC therapies. www.impactjournals.com/oncotarget
Joaquim Bosch-Barrera is the recipient of a Grant from the Health Research and Innovation Strategic Plan (SLT006/17/114; PERIS 2016-2020; Pla stratègic de recerca i innovació en salut; Departament de Salut ...doi:10.18632/aging.102646 pmid:31901900 pmcid:PMC6977679 fatcat:s4jyajnekrdv5dc54ta7fp3s4m
KRAS mutations are an established predictor of lack of response to EGFRtargeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab fromdoi:10.18632/oncotarget.11985 pmid:27636997 pmcid:PMC5347684 fatcat:lhcgxvve7zbb3jthiab3ux5oj4
more »... iting mCRC growth. NRAS Q61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRAS Q61K/+ from cetuximab-sensitive NRAS +/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRAS Q61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRAS Q61K/+ cells to MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors.
Elisabet Cuyàs holds a research contract "Miguel Servet" (CP20/00003) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (Spain). ... Joaquim Bosch-Barrera is the recipient of Research Grants from Grupo Español de Cáncer de Pulmón (GECP), La Marató de TV3 foundation (201906), and the Health Research and Innovation Strategic Plan (SLT006 ...doi:10.3390/ph15010019 pmid:35056076 pmcid:PMC8778965 fatcat:5xt5f4nserdynkmor42si7vzim
Denosumab, a monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), might be a novel preventative therapy for BRCA1-mutation carriers at high risk of developing breast cancer. Beyond its well-recognized bone-targeted activity impeding osteoclastogenesis, denosumab has been proposed to interfere with the cross-talk between RANKL-producing sensor cells and cancer-initiating RANK + responder cells that reside within premalignant tissues of BRCA1-mutation carriers. Wedoi:10.18632/oncotarget.16558 pmid:28388533 pmcid:PMC5471031 fatcat:vpbdkscshbee5iuxo66kgkcpru
more »... ein tested the alternative but not mutually exclusive hypothesis that BRCA1 deficiency might cell-autonomously activate RANKL expression to generate cellular states with cancer stem cell (CSC)-like properties. Using isogenic pairs of normallike human breast epithelial cells in which the inactivation of a single BRCA1 allele results in genomic instability, we assessed the impact of BRCA1 haploinsufficiency on the expression status of RANK and RANKL. RANK expression remained unaltered but RANKL was dramatically up-regulated in BRCA1 mut/+ haploinsufficient cells relative to isogenic BRCA1 +/+ parental cells. Neutralizing RANKL with denosumab significantly abrogated the ability of BRCA1 haploinsufficient cells to survive and proliferate as floating microtumors or "mammospheres" under non-adherent/non-differentiating conditions, an accepted surrogate of the relative proportion and survival of CSCs. Intriguingly, CSC-like states driven by epithelial-to-mesenchymal transition or HER2 overexpression traits responded to some extent to denosumab. We propose that breast epithelium-specific mono-allelic inactivation of BRCA1 might suffice to cellautonomously generate RANKL-addicted, denosumab-responsive CSC-like states. The convergent addiction to a hyperactive RANKL/RANK axis of CSC-like states from www.impactjournals.com/oncotarget/ Oncotarget 35020 www.impactjournals.com/oncotarget genetically diverse breast cancer subtypes might inaugurate a new era of cancer prevention and treatment based on denosumab as a CSC-targeted agent.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. SUMMARY "The dose makes the poison", the common motto of toxicology first expressed by Paracelsus more than 400 years ago, may effectively serve to guide potential applications for metformin and related biguanides in oncology. While Paracelsus' law for thedoi:10.18632/oncotarget.1965 pmid:24909934 pmcid:PMC4058009 fatcat:4lzsphmztbdbrmu6fjzqsq2mra
more »... sponse effect has been commonly exploited for the use of some anti-cancer drugs at lower doses in non-neoplastic diseases (e.g., methotrexate), the opposite scenario also holds true; in other words, higher doses of non-oncology drugs, such as anti-diabetic biguanides, might exert direct antineoplastic effects. Here, we propose that, as for any drug, there is a dose range for biguanides that is without any effect, one corresponding to "diabetobiguanides" with a pharmacological effect (e.g., insulin sensitization in type 2 diabetes, prevention of insulin-dependent carcinogenesis, indirect inhibition of insulin and growth factor-dependent cancer growth) but with minimal toxicity and another corresponding to "oncobiguanides" with pharmacological (i.e., direct and strong anticancer activity against cancer cells) as well as toxic effects. Considering that biguanides demonstrate a better safety profile than most oncology drugs in current use, we should contemplate the possibility of administering biguanides through non-conventional routes (e.g., inhaled for carcinomas of the lung, topical for skin cancers, intravenous as an adjunctive therapy, rectal suppositories for rectal cancer) to unambiguously investigate the therapeutic value of high-dose transient biguanide exposure in cancer. Perhaps then, the oncobiguanides, as we call them here, could be viewed as a mechanistically different type of anti-cancer drugs employed at doses notably higher than those used chronically when functioning as diabetobiguanides. The antimetabolite drug methotrexate (MTX) was originally developed as an anti-cancer agent and, as such, received U.S. Food and Drug Administration (FDA) approval in 1953. Not long afterwards, MTX was found to exert symptomatic control of severe, recalcitrant, disabling psoriasis; the FDA officially approved MTX as a treatment for psoriasis in the early 1970's. Today, MTX is a well-known chemotherapeutic and immunosuppressive agent that is widely and successfully used in many rheumatologic, dermatologic, and hematologic diseases  . Notably, the clinical use of MTX represents a paradigmatic example of Paracelsus' law, which states "sola dosis facit venenum (only dose makes the poison)", meaning that the right dose differentiates a poison from a remedy; hence, a molecule becomes a drug if the dose required to treat a complication is pharmacologically active with minimal toxicity. The so-called Paracelsus' "dose-response effect" establishes that, for any drug, there is a dose range (concentration) that is without any effect, one with a pharmacological effect but minimal toxicity (or an acceptable safety profile), and another with pharmacological and toxic effects. In the case of MTX, experience in multiple sclerosis indicates that the low dose of 7.5 mg per square meter (m 2 ) per week (0.1 mg kg -1 ) for up to 2 years is not associated with toxicity. The use of doses of MTX up to 30 mg per week (0.4 mg kg -1 ) in the treatment of juvenile and rheumatoid arthritis and psoriasis is associated with an acceptable toxicity profile.
Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes ofdoi:10.3389/fendo.2018.00657 pmid:30459716 pmcid:PMC6232372 fatcat:rqhrzsbpbvcu3htlyls3bxfpua
more »... tformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD + binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD + hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD + in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD + levels decline.
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