259 results found
Varghese V, Magnani L, Harada-Shoji N, et al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression., Sci Rep, Vol: 9
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Zhang B, Lam EW-F, Sun Y, 2019, Senescent cells: A new Achilles' heel to exploit for cancer medicine?, Aging Cell, Vol: 18
Cellular senescence is a typical tumor-suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging-related disorders principally via the senescence-associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti-aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications.
Lam E, The Prognostic Landscape of Interactive Biological Processes Presents Treatment Responses in Cancer, EBioMedicine, ISSN: 2352-3964
Cui B, Luo Y, Tian P, et al., 2019, Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells., J Clin Invest
Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.
Parzych K, Saavedra-García P, Valbuena GN, et al., 2019, The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation., Oncogene
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
FOXO3 is a tumor suppressor that orchestrates the expression of genes that regulate cell cycle progression, apoptosis, metabolism, oxidative stress, and other important cellular processes. Its inactivation is closely associated with tumorigenesis and cancer progression. On the other hand, sirtuin proteins have been demonstrated to be able to deacetylate, thus causing FOXO3 inactivation at the posttranslational level. Therefore, targeting sirtuin proteins renders new avenues for breast cancer treatment. Here, we describe three procedures for studying FOXO3 posttranslational modifications controlled by sirtuin proteins in cancer cells.
Intuyod K, Saavedra-Garcia P, Zona S, et al., 2018, FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance, CELL DEATH & DISEASE, Vol: 9, ISSN: 2041-4889
Vervoort SJ, de Jong OG, Roukens MG, et al., 2018, Gloal transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis, ELIFE, Vol: 7, ISSN: 2050-084X
Lam E, Chronic stress-induced lactate hydrogenase A promotes stem-like properties in breast cancer cells, Journal of Clinical Investigation, ISSN: 0021-9738
Chronicstress triggers activation of the sympathetic nervous system (SNS) and drives malignancy. Using an immunodeficient murine system, we showed that chronicstress-induced epinephrine promotedbreast cancer stem-like properties via lactate dehydrogenase A(LDHA) dependent metabolic rewiring. Chronicstress-induced epinephrine activated LDHA to generate lactate and the adjusted pHdirected USP28-mediated deubiquitination and stabilization of MYC. The SLUGpromoter was then activated by MYC which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C.Thesefindings demonstrated the critical importance ofpsychologicalfactors in promoting stem-like properties in breast cancer cells. As such,the LDHA-lowering agent, vitamin C, can be a potentialapproachfor12combating the stress-associated breast cancer.
Li M, Chai H-F, Peng F, et al., 2018, Estrogen receptor beta upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma, CELL DEATH & DISEASE, Vol: 9, ISSN: 2041-4889
Wahba J, Natoli M, Whilding LM, et al., 2018, Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer, CANCER IMMUNOLOGY IMMUNOTHERAPY, Vol: 67, Pages: 1753-1765, ISSN: 0340-7004
Phoomak C, Silsirivanit A, Park D, et al., 2018, O-GlcNAcylation mediates metastasis of cholangiocarcinoma through FOXO3 and MAN1A1, ONCOGENE, Vol: 37, Pages: 5648-5665, ISSN: 0950-9232
Chen F, Long Q, Fu D, et al., 2018, Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Sun Y, Coppe J-P, Lam EW-F, 2018, Cellular Senescence: The Sought or the Unwanted?, TRENDS IN MOLECULAR MEDICINE, Vol: 24, Pages: 871-885, ISSN: 1471-4914
Gong C, Man EPS, Tsoi H, et al., 2018, BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen-Resistant Breast Cancer, CLINICAL CANCER RESEARCH, Vol: 24, Pages: 3681-3691, ISSN: 1078-0432
Yao S, Fan LY-N, Lam EW-F, 2018, The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance, SEMINARS IN CANCER BIOLOGY, Vol: 50, Pages: 77-89, ISSN: 1044-579X
Laphanuwat P, Likasitwatanakul P, Sittithumcharee G, et al., 2018, Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence, JOURNAL OF CELL SCIENCE, Vol: 131, ISSN: 0021-9533
Laphanuwat P, Likasitwatanakul P, Sittithumcharee G, et al., 2018, Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence, Journal of Cell Science, Vol: 131, ISSN: 0021-9533
© 2018. Published by The Company of Biologists Ltd. Expression of cyclin D1 (CCND1) is required for cancer cell survival and proliferation. This is presumably due to the role of cyclin D1 in inactivation of the RB tumor suppressor. Here, we investigated the pro-survival function of cyclin D1 in a number of cancer cell lines. We found that cyclin D1 depletion facilitated cellular senescence in several cancer cell lines. Senescence triggered by cyclin D1 depletion was more extensive than that caused by the prolonged CDK4 inhibition. Intriguingly, the senescence caused by cyclin D1 depletion was independent of RB status of the cancer cell. We identified a build-up of intracellular reactive oxygen species in the cancer cells that underwent senescence upon depletion of cyclin D1 but not in those cells where CDK4 was inhibited. The higher ROS levels were responsible for the cell senescence, which was instigated by the p38-JNKFOXO3a- p27 pathway. Therefore, expression of cyclin D1 prevents cancer cells from undergoing senescence, at least partially, by keeping the level of intracellular oxidative stress at a tolerable sublethal level. Depletion of cyclin D1 promotes the RB-independent pro-senescence pathway and the cancer cells then succumb to the endogenous oxidative stress levels.
Zhang B, Fu D, Xu Q, et al., 2018, The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
de Moraes GN, Ji Z, Fan LY-N, et al., 2018, SUMOylation modulates FOXK2-mediated paclitaxel sensitivity in breast cancer cells, ONCOGENESIS, Vol: 7, ISSN: 2157-9024
Peng F, Wang J-H, Fan W-J, et al., 2018, Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia, ONCOGENE, Vol: 37, Pages: 1062-1074, ISSN: 0950-9232
Peng F, Wang J-H, Fan W-J, et al., 2018, Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia (vol 37, pg 1062, 2017), ONCOGENE, Vol: 37, Pages: 1119-1119, ISSN: 0950-9232
Saavedra-Garcia P, Fan LY-N, Lam EW-F, 2018, Multifaceted link between metabolism and cancer, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 65-66, ISSN: 0303-7207
Saavedra-Garcia P, Nichols K, Mahmud Z, et al., 2018, Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 82-92, ISSN: 0303-7207
Alasiri G, Fan LY-N, Zona S, et al., 2018, ER stress and cancer: The FOXO forkhead transcription factor link, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 67-81, ISSN: 0303-7207
Monteiro LJ, Cubillos S, Sanchez M, et al., 2018, Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia., Reprod Sci
Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions and to exhibit analogous vascular, proliferative, migratory, and invasive capacities. Thus, genes that are important for tumorigenesis, such as forkhead box M1 ( FOXM1) may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and messenger RNA (mRNA) levels decreased as gestational age increased in rat's placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its highest expression at 3% oxygen tension, which reflects early implantation environment, and dropping to very low levels at 1% O2. Remarkably, FOXM1 silencing in JEG-3 cells was able to significantly decrease migration by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, angiogenesis was compromised when conditioned media (CM) from FOXM1-siRNA -JEG-3 (3% O2) was added to human umbilical vein endothelial cells (HUVEC) cells; however, when CM of JEG-3 cells overexpressing FOXM1 at 1% O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, quantitative real-time polymerase chain reaction (PCR) assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3% O2 and overexpression of FOXM1 at 1% O2 led to downregulation and upregulation of vascular endothelial growth factor transcriptional (VEGF) levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia (PE). Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes and that under chronic hypoxic conditions (1% O2) and in patients with severe PE, its levels decrease.
Asaduzzaman M, Constantinou S, Min H, et al., 2018, Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer (vol 163, pg 461, 2017), BREAST CANCER RESEARCH AND TREATMENT, Vol: 167, Pages: 605-606, ISSN: 0167-6806
Roig B, Rodriguez-Balada M, Samino S, et al., 2017, Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Lyu Y, Lou J, Yang Y, et al., 2017, Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and - independent pathways, LEUKEMIA, Vol: 31, Pages: 2543-2551, ISSN: 0887-6924
Li S-S, Xu L-Z, Zhou W, et al., 2017, p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis, CARCINOGENESIS, Vol: 38, Pages: 1092-1103, ISSN: 0143-3334
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