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At least 19 recordsLinked to original sources
PubMed2026

Epithelial-Mesenchymal Transition Shapes the Lipotoxic Response of Colon Cancer Cells to Palmitic Acid.

Saturated fatty acids such as palmitic acid (PA) can induce lipotoxic stress, whereas monounsaturated fatty acids like oleic acid (OA) often promote adaptive responses through lipid droplets (LDs) formation. Here, we reveal that epithelial-mesenchymal transition (EMT) profoundly influences the lipotoxic response of colorectal cancer cells. Using the epithelial-like HCT15 and mesenchymal-like HCT116 cell lines, we combined proteomic, metabolic, and imaging analyses to elucidate how EMT status determines lipid storage capacity and resistance to PA-induced toxicity. A basal proteomic profiling highlighted a striking divergence in metabolic changes: HCT15 cells displayed enhanced glycolysis and reduced expression of LDs biogenesis proteins, while HCT116 cells exhibited oxidative metabolism and a "lipid-rich" proteomic signature enriched in PLIN2, GPAT3, and DGAT1. Functionally, PA triggered massive cytotoxicity and failed to induce LDs in HCT15 cells, correlating with DGAT1/2 downregulation and suppressed triacylglycerol synthesis. In contrast, HCT116 cells showed modest LDs accumulation, preserved mitochondrial function, and strong resistance to lipotoxic stress. OA treatment restored LDs formation and cell viability in both models, underscoring the protective role of unsaturated fatty acids. Notably, forced EMT induction in HCT15 cells by PMA markedly enhanced LDs accumulation and reduced PA-induced death, confirming that EMT confers metabolic plasticity and lipid-buffering capacity. These findings demonstrate that EMT status modulates differential lipid handling and stress adaptation in colon cancer cells, linking mesenchymal transition to enhanced LDs biogenesis and survival under lipotoxic conditions. Data are available via ProteomeXchange with identifier PXD071641.

Humans↗
PubMed1992

Lipofectin enhances cellular uptake of antisense DNA while inhibiting tumor cell growth.

A natural DNA oligomer (15-mer) was synthesized with a sequence complementary to the translation initiation codon region of the human TGF-alpha mRNA and mixed with Lipofectin to form unilamellar complexes. It was found that tumor cell growth was inhibited when HCT116 cells were treated with Lipofectin-DNA oligomer complexes or with Lipofectin alone. Uptake of 32P-labeled 15-mers into colon tumor cells was compared in the presence and absence of Lipofectin. The amount of labeled oligomer found in cells that received optimal ratios of Lipofectin to DNA was 4- to 10-fold higher than the amount found in cells that received 32P-labeled DNA alone. Although Lipofectin-antisense DNA oligomer treatment of HCT116 cells caused a dose-dependent inhibition of cell growth, there was a subsequent rise in target mRNA product. Because the mechanism of growth inhibition could not involve an inhibition of TGF-alpha expression, it was concluded that Lipofectin probably exerts a nonspecific, detergent-like effect upon the cell membrane, producing an enhancement of TGF-alpha processing and release.

Base Sequence↗
PubMed2026

Assessment the Effects of Roasted and Non-Roasted Coffee Extracts on Colon Cancer Cells.

Coffee extracts contain numerous bioactive compounds. Given the dietary link between coffee consumption and colorectal cancer, this study compared the effects of roasted and green (unroasted) coffee extracts on human colorectal cancer cells (HCT116) and non-cancerous fibroblasts (BJ-5ta) to evaluate how processing influences proliferation and molecular signaling. Real-time cell analysis (RTCA), qRT-PCR, and label-free quantitative proteomic analysis were performed to assess cellular responses. MTS and RTCA showed that in BJ-5Ta fibroblasts, coffee extracts increased proliferation in the order CNR < CAR < CAU < CNU, whereas the trend was reversed in HCT116 cancer cells. Proteomic analysis revealed that in BJ-5Ta cells, unroasted coffee extract caused downregulation of the ribosome pathway, and natural coffee extract caused downregulation of the gap junction pathway, indicating reduced protein synthesis and cell-cell communication as a potential stress-adaptive response. In contrast, in HCT116 cells, unroasted coffee extract upregulated the ribosome pathway. Also, natural coffee extract upregulated the pentose phosphate pathway in HCT116 cells, which may enhance NADPH production and reduce oxidative stress. Current evidence suggests coffee's bioactive compounds may have different effects varying by coffee extract type and their preparation.

Humans↗
PubMed1992

Occupancy of the cancer cell urokinase receptor (uPAR): effects of acid elution and exogenous uPA on cell surface urokinase (uPA).

The development of a simple, sensitive fluorimetric assay for the measurement of cell surface-associated urokinase plasminogen activator (uPA) on viable, adherent HCT116 cells in microtitre plates, after a preincubation with purified human plasminogen is described. The assay determines plasmin activity by the cleavage of H-D-Val-Leu-Lys 4-aminomethyl coumarin under near physiological pH and ionic conditions with a sensitivity in the range of 5-100 mIU uPA/well at excitation 355 nm and emission 460 nm. Plasmin generated during the assay converted all cell-surface sc-uPA to tc-uPA, allowing the determination of total uPA activity. Inhibitor studies (PAI-2, amiloride or Glu-Gly-Arg chloromethylketone) confirmed the specificity of the uPA assay. Removal of these agents prior to assay allowed determination of the cell surface sc-uPA:tc-uPA ratio. Cell surface activity was only partially removed by acid elution. This corresponded with the loss of a number of proteins and uPA-containing species as detected by SDS-PAGE, gelatin enzymography and Western blotting. Although the major protein species eluted had a M(r) of 55 kDa, reacted with a commercial anti-human uPA mAb and correlated with the main lytic zone, other higher M(r) species were also eluted from HCT116 cells. Exogenous uPA increased cell-surface activity markedly on cells previously treated with acid. Following acid elution, cell surface uPA activity was restored after 30h in culture suggesting either de novo synthesis or release of pre-formed uPA with subsequent secretion and binding to uPAR. The assay has enabled studies on adherent cells to address questions about the regulation and expression of cell-surface uPA.

Aprotinin↗
PubMed2026

Novel environmental contaminant 6PPD-quinone promotes malignant phenotypes in colorectal cancer cells and identifies candidate response-associated genes.

6PPD-quinone (6PPDQ), an oxidative transformation product of the widely used tire antioxidant 6PPD, is a ubiquitous environmental contaminant with bioaccumulation potential and widespread human exposure. Recent epidemiological evidence indicates a positive association between urinary 6PPDQ levels and colorectal cancer (CRC) risk; however, its biological effects on CRC-related phenotypes and associated molecular responses remain unclear. We integrated bioinformatics analysis, prognostic modeling, molecular docking and dynamics simulations, and in vitro experiments to investigate cellular and molecular responses to 6PPDQ in CRC models. Predicted 6PPDQ targets were intersected with CRC prognosis-related genes from The Cancer Genome Atlas, followed by functional enrichment and LASSO regression to construct a prognostic risk model, with 1-, 3-, and 5-year AUC values of 0.727, 0.754, and 0.778, respectively. Molecular docking and 100-ns molecular dynamics simulations suggested interactions between 6PPDQ and candidate proteins, including CPT2, SHC2, SRMS, and STK35. Functional assays showed that 6PPDQ exposure altered proliferation, wound-closure capacity, and invasion in Caco-2 and HCT116&#x202f;cells across the nanomolar concentration range, with non-monotonic and cell-line-dependent responses. In contrast, NCM460&#x202f;cells showed no increase in EdU incorporation at 10 or 100&#x202f;nM, whereas reduced proliferation at higher concentrations was accompanied by increased LDH release. 6PPDQ also altered the expression of several prognosis-associated candidate genes. These findings identify cellular phenotypes and candidate molecular responses associated with 6PPDQ exposure under the tested in vitro conditions, but do not establish their causal roles or in vivo relevance. Further mechanistic and in vivo studies are required.

Humans↗
PubMed2026

LncRNA RP11-708J19.2 promotes colorectal cancer progression by binding to SIRT7 via regulating H3K18ac.

Colorectal cancer (CRC) is a prevalent malignancy with a complex genetic basis. Recent genome-wide association studies (GWAS) have identified a susceptibility locus at 3p21.31, however, the functional SNP(s) underlying the association between the 3p21.31 region and CRC remain to be elucidated. In this study, we identified rs2101247 as the potential functional SNP and further demonstrated that rs2101247 is significantly associated with the expression of the nearby long non-coding RNA (lncRNA) RP11-708J19.2 (ENSG00000271161.1). Functional experiments showed that RP11-708J19.2 is upregulated in CRC tumor tissues, and its knockdown reduces cell viability while promoting apoptosis in SW1116 and HCT116 cell lines. Mechanistically, RP11-708J19.2 interacts directly with the deacetylase SIRT7, modulating histone H3K18 acetylation (H3K18ac). Specifically, RP11-708J19.2 knockdown leads to a significant upregulation of H3K18ac levels, implicating a SIRT7-mediated epigenetic pathway in CRC progression. Our findings elucidate a novel functional SNP-lncRNA axis that contributes to CRC pathogenesis, providing potential biomarkers for early detection and therapeutic targets for intervention.

Humans↗
PubMedDate not supplied

Modulation of differentiation-related responses in human colon carcinoma cells by protein kinase inhibitor H-7.

1-(isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), a potent inhibitor of protein kinases, has been used as a tool to examine the role of protein kinases in a variety of cellular functions. Contingent on the cell type, H-7 has been reported either to inhibit or to promote differentiation. The biological effects of H-7 on human colon adenocarcinoma cells have not been reported. In this study we investigated the effects of H-7 on differentiation - related parameters such as cellular morphology, proliferation, the expression of carcinoembryonic antigen (CEA), fibronectin and cytokeratins in human adenocarcinoma cell lines HCT116 and SW480. H-7 induced pronounced morphological alterations in both cell lines. It induced fibronectin expression and down-modulated CEA expression and secretion in the SW480 cells, but not in the HCT116 cells. Expression of acidic keratins was not affected by H-7 treatment in both cell lines. However, the expression of basic keratins were down-modulated in the HCT116 cells and enhanced in the SW480 cells. These studies showed that the protein kinase inhibitor, H-7, modulated phenotypic properties in human colon adenocarcinoma cells. Alterations in phenotypic properties and their significance in regard to the induction of differentiation are discussed.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2026

Genome-Wide In Vivo RNAi Screening Identifies HOXD4 as a Tumor Metastasis Suppressor in Colorectal Cancer.

Metastasis remains a major therapeutic challenge in colorectal cancer, highlighting an urgent need to elucidate its underlying molecular mechanisms. In this study, an in vivo screening system integrating genome-wide short hairpin RNA library and next-generation sequencing identifies six candidate metastasis suppressors, among which Homeobox D4 (HOXD4) shows the most pronounced effects. Clinicopathological analyses reveal significant HOXD4 downregulation in tumor tissues relative to adjacent normal tissues, with reduced expression strongly correlating with aggressive tumor features. Functional assays demonstrate that HOXD4 depletion enhances migration, invasion, and tumorsphere formation in HCT116 cells, while ectopic HOXD4 overexpression reverses these malignant phenotypes in SW620 cells. Mechanistically, HOXD4 suppresses epithelial-mesenchymal transition (EMT) by directly binding to the promoter of Forkhead box Q1 (FOXQ1), a key driver of EMT and stemness, and thereby transcriptionally repressing its expression. Immunohistochemistry confirms an inverse correlation between HOXD4 and FOXQ1 expression in clinical specimens. Rescue experiments substantiate that HOXD4 exerts its metastasis-suppressing functions via FOXQ1 regulation. Collectively, these findings not only establish an efficient platform for screening tumor metastasis suppressors, but also identify HOXD4 as a master transcriptional regulator of the FOXQ1-EMT axis, providing a promising target for metastasis interception.

Humans↗
PubMed2025

CCT8 drives colorectal cancer progression via the RPL4-MDM2-p53 axis and immune modulation.

PURPOSE: Colorectal cancer (CRC) ranks high in global mortality, emphasizing the need for effective interventions. The aim of the research is to elucidate the oncogenic role of CCT8 in CRC and its interaction with RPL4 in the RPL4-MDM2-p53 axis. METHODS: TIMER 2.0, TCGA, and GTEx databases were used to analyze CCT8 expression patterns in CRC. Immunohistochemistry was performed to examine CCT8 distribution in CRC tissues and adjacent non-tumor tissues. Functional assays, including CCK-8, transwell, wound-healing, and flow cytometry, were conducted using DLD-1 and HCT116 cell lines to assess the effects of CCT8 on cell proliferation, migration, invasion, and apoptosis. Gene set enrichment analysis, protein-protein interaction network analysis, and co-immunoprecipitation were performed to explore the interaction between CCT8 and RPL4 and their role in the RPL4-MDM2-p53 pathway. Additionally, gene set variation analysis was applied to investigate the relationship between CCT8/RPL4 expression and immune infiltration patterns in CRC. RESULTS: CCT8 was significantly upregulated in CRC and associated with tumor progression. Mechanistically, CCT8 potentially synergizes with RPL4 concluded from their positive correlation and similar immune infiltration patterns, influencing the RPL4-MDM2-p53 axis and contributing to p53 ubiquitination and degradation. CONCLUSION: These findings underscore the oncogenic significance of CCT8 in CRC and shed light on its molecular mechanisms, paving the way for potential therapeutic applications.

Humans↗
PubMed1992

Inhibition of colon tumor cell growth by 8-chloro-cAMP is dependent upon its conversion to 8-chloro-adenosine.

Recent interest in site-selective cAMP analogs has focused on the role of 8-chloro-adenosine (8-Cl-adenosine) in the inhibition of tumor cell growth by 8-chloro-cAMP (8-Cl-cAMP) (Van Lookeren Campagne, et al. Cancer Res 1991; 51: 1600-5). We have evaluated 8-Cl-cAMP and 8-Cl-adenosine for their growth inhibitory activity against two human colon adenocarcinoma cell lines, HCT116 and FET. Because these cell lines have been adapted to grow in chemically defined medium we were able to evaluate the effect of serum on 8-Cl-cAMP's growth inhibitory activity. In addition, cells grown in serum-free medium were tested for their sensitivity to 8-Cl-cAMP, serum-activated 8-Cl-cAMP and 8-Cl-adenosine. IC50 values, determined by measuring cell growth using a MTT colorimetric assay, showed that 'serum activation' of 8-Cl-cAMP was required to achieve inhibition of HCT116 (IC50 = 1.3 +/- 0.1 microM) and FET (IC50 = 2.0 +/- 0.1 microM) cell growth. IC50 values were not reached at the highest concentrations tested (IC50 > 500 microM) in the absence of serum, permitting us to conclude that 8-Cl-cAMP does not have growth inhibitory activity between 1.0 and 500 microM doses. HCT116 and FET cells grown in media containing serum and in the presence of 8-Cl-adenosine had IC50 values of 0.6 +/- 0.1 and 0.9 +/- 0.2 microM, respectively. HCT116 and FET cells grown in chemically defined medium containing 8-Cl-adenosine exhibited IC50 values of 1.0 +/- 0.1 and 3.1 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed2026

UBE2D4 Upregulation Promotes Cuproptosis Sensitivity in Colorectal Cancer.

BACKGROUND: Cuproptosis, a copper-dependent form of regulated cell death, represents a potential therapeutic vulnerability in colorectal cancer (CRC). However, the regulatory mechanisms governing cuproptosis in CRC remain largely unknown. METHODS: UBE2D4 expression was analyzed in the TCGA-COAD cohort and validated in CRC cell lines (HCT116, HT29) and normal colon epithelial cells (FHC) by qRT-PCR and western blot. Paired CRC and adjacent normal tissues (n&#x2009;=&#x2009;5) were also examined by western blot. UBE2D4-knockdown HT29 cells were generated by transient siRNA transfection to assess cell viability (CCK-8), migration (wound healing assay), and expression of cuproptosis-related genes (DLAT, HSP70, LIAS) under copper overload conditions (elesclomol+CuSO4). RESULTS: UBE2D4 was significantly upregulated in CRC tissues and cell lines compared to normal controls. In paired clinical samples, western blot confirmed that UBE2D4 protein expression was elevated in tumor tissues, accompanied by increased DLAT, HSP70 and LIAS. Copper overload induced typical cuproptotic mitochondrial morphology and triggered a marked upregulation of UBE2D4, DLAT, and HSP70, alongside downregulation of LIAS. UBE2D4 silencing had no effect on baseline cell viability or migration but significantly rescued cells from copper-induced cytotoxicity. Genetically, UBE2D4 knockdown specifically attenuated the copper-induced elevation of DLAT, while restoring HSP70 and LIAS to near-baseline levels. CONCLUSION: These findings identify UBE2D4 as a genetically upregulated and functionally significant gene in colorectal cancer. Its upregulation correlates with altered expression of cuproptosis-related genes, particularly DLAT, suggesting that UBE2D4 expression status may represent a genetic determinant of cuproptosis sensitivity in CRC. This study provides a genetic basis for stratifying CRC patients who might benefit from copper-based therapeutic strategies.

Humans↗
PubMed1992

Regulation of human colon-carcinoma cell adhesion to extracellular matrix by transforming growth factor beta 1.

The regulatory effect of transforming growth factor beta 1 (TGF-beta 1) on the adhesion of human colon-carcinoma cells to the extracellular matrix (ECM) was investigated. ECMs used in this study included tissue-culture wells coated with fibronectin, laminin, collagen and BSA, as well as plastic wells. Three phenotypically different human colon-carcinoma cell lines (Moser, HCT116, and KM12SM) were used. The Moser cell line is moderately differentiated and, in terms of the diversity of responses elicited by TGF-beta 1, is the human colon-carcinoma cell line most responsive to TGF-beta 1 as reported to date. By comparison, the undifferentiated HCT116 and the highly metastatic KM12SM cells are unresponsive to this growth factor. We showed that TGF-beta 1 regulated the adhesion responses of all 3 cell lines. However, the response profiles as well as the endogenous adhesive properties of each cell line were quite different from those of the others. Endogenous Arg-Gly-Asp(RGD)-related receptors were present on the HCT116 but not on the other cells. The observed regulatory effect of TGF-beta 1 was contingent on the cell line, the type of ECM, and the growth-factor treatment protocol used. When cells were treated with TGF-beta 1 for 16 hr prior to exposure to ECM in a 4-hr adhesion assay, a significant increase in adhesion to fibronectin and collagen was observed for the Moser cells. For the identical experimental protocol, the KM12SM cells responded by increasing adhesion to fibronectin, while the HCT116 cells responded by decreasing adhesion to collagen. Kinetic analyses of TGF-beta 1 treatment showed that increased adhesion response to laminin was induced in the Moser cells after 2 hr of growth-factor treatment. This response declined rapidly upon further exposure of the cells to TGF-beta 1. Simultaneous exposure of cells to both TGF-beta 1 and ECM negated the adhesion responses described above. The up-modulation of adhesion to fibronectin, laminin and collagen by TGF-beta 1 was mediated through RGD-related integrin receptors. RGD-containing peptides effectively blocked the enhanced adhesion responses induced by TGF-beta 1.

Amino Acid Sequence↗
PubMed2025

Oncoproteins E6/E7 of the human papillomavirus types 16 & 18 synergize in modulating oncogenes and tumor suppressor proteins in colorectal cancer.

OBJECTIVE: Our study presents a novel analysis of the oncogenes and tumor suppressor proteins directly modulated by E6/E7 of high-risk HPV types 16 and 18, in colorectal cancer (CRC). METHODS: HCT 116 (KRAS mutant) & HT-29 (TP53 mutant) cell models of CRC were transduced with E6/E7 of HPV16 and HPV18, individually and in combination. Further, we utilized a liquid chromatography mass spectrometry (LC-MS/MS) approach to analyze and compare the proteomes of both CRC cell models. RESULTS: We generated six stably transduced cell lines. Our data revealed a significantly higher, HPV-induced modulation of oncogenes and tumor suppressor proteins in the TP53 mutant model, as compared to the KRAS mutant model (p&#x2009;&#x2264;&#x2009;0.01). Less than 1% of the genes were commonly modulated by HPV, between both models. We also report that HT-29 cells, expressing E6/E7 of both HPV types, significantly reduced the suppression of oncogenes as compared to cells expressing E6/E7 of either HPV types individually (p-value &#x2264;0.00001). CONCLUSION: Our data imply that HPV coinfections leads to the sustenance of a pro-oncogenic environment in CRC. HPV modulates different oncogenes/tumor suppressor proteins in CRC of varying mutational backgrounds, thus highlighting the importance of personalized therapies for such diseases with mutational heterogeneity.

Humans↗
PubMed2026

Polysomal Profiling Coupled to Allele-Specific Proteomics Reveals an EIF4H TranSNP Allele Possessing Higher mRNA Translation Potential.

To search for genetic sources of allele-specific mRNA translation, we leveraged heterozygous polymorphisms and variants present in the exome of HCT116 colorectal adenocarcinoma-derived cells, computing allelic fractions from both total and polysome-associated RNA from RNA-Seq data. Allelic imbalance in polysomal RNA led us to nominate 52 coding variants associated with allele-specific mRNA translation, of which 16 are nonsynonymous. To validate instances of allele-specific translation, a proteomics workflow was developed that combines label-free shotgun analysis, high-pH reversed-phase peptide fractionation, and targeted parallel reaction monitoring using isotope-labeled peptide standards. Using this approach, we provide proof-of-concept validation of the heterozygous G>A, R183H missense single-nucleotide variant rs1554710467 in the eukaryotic initiation factor 4H (EIF4H) gene. The variant is present in two EIF4H alternatively spliced variants, which showed equivalent translation efficiency in HCT116 cells but differ in abundance. The alternative peptide containing H183 was significantly more abundant than the corresponding reference peptide containing R183, consistent with the over-representation of the alternative allele in polysomal RNA in HCT116 cells. A dual-fluorescence ribosome-stalling assay confirmed the enhanced translation potential of the variant allele. The two EIF4H allelic proteins exhibited similar stability and subpolysomal localization. This study demonstrates the feasibility of using allele-specific proteomics at the endogenous protein levels by exploiting heterozygous coding variants. Overall, our approach extends the toolbox available to investigate allele-specific differences in mRNA translation potential, a relatively underexplored layer of gene expression regulation that could reveal interindividual differences in disease-relevant phenotypes.

Humans↗
PubMed2026

ZNF695 Promotes Colorectal Cancer Progression Through Transcriptional Activation of CBX8 and Subsequent Wnt/&#x3b2;-Catenin Signaling Activation.

In this investigation, we examined the functional mechanism of the transcription factor zinc finger protein 695 (ZNF695) and its target gene chromobox protein homolog 8 (CBX8) in colorectal cancer (CRC) migration and invasion. HCT-116 and LOVO cell lines were used to establish cell models with knocked-down ZNF695 and knocked-down or over-expressed CBX8. To comprehensively evaluate the functional contributions of ZNF695 and CBX8 to cellular phenotypes, we employed CCK-8, wound-healing, and Transwell assays to evaluate cell proliferation, migration, and invasion, respectively. To assess the impact of ZNF695 on tumor progression, we generated a xenograft model utilizing nude mice. A FLAG-ZNF695 expression plasmid was constructed, and ChIP-seq experiments were performed. By integrating mRNA sequencing data following ZNF695 knockdown with highly expressed genes in CRC from the TCGA database, CBX8 was identified as a putative downstream target of ZNF695. We employed a dual-luciferase reporter assay to validate the specific binding affinity of ZNF695 toward the CBX8 promoter region. To elucidate the specific biological cascades modulated by ZNF695 and CBX8, we conducted a comprehensive pathway enrichment analysis. Rescue experiments were conducted to determine whether the ZNF695/CBX8 regulatory axis upregulates the expression of the Wnt signaling pathway downstream targets, AXIN2 and CCND1. Both in vitro assays and in vivo models confirmed that silencing ZNF695 dramatically suppresses CRC cell proliferation, migration, and invasion, while concurrently impeding tumor progression. ChIP-seq coupled with dual-luciferase reporter assays substantiated the direct binding of ZNF695 to the CBX8 promoter. Furthermore, CBX8 depletion significantly attenuated the migratory and invasive phenotypes of CRC cells. Restoring CBX8 expression effectively rescued the migratory and invasive deficits in CRC cells induced by ZNF695 silencing. Re-expression of CBX8 in ZNF695-silenced cells restored Wnt/&#x3b2;-catenin signaling activity, accompanied by increased expression of AXIN2 and CCND1. ZNF695 promotes CRC progression by transcriptionally activating CBX8 and subsequently enhancing Wnt/&#x3b2;-catenin signaling, thereby promoting tumor cell proliferation, migration, and invasion.

Humans↗
PubMed1992

Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents in human colon tumor cell lines.

Six human colon tumor cell lines were analyzed for their constitutive levels of the c-myc protein. The nuclear proto-oncogene, c-myc, was detected as an expressed product in all of the human colon tumor cell lines analyzed. The poorly differentiated cell lines HCT116, RKO and C showed c-myc levels that averaged 2-fold greater than their well-differentiated counterparts, i.e., GEO, CBS and FET. When c-myc levels and responses to serum induction were analyzed in the presence of inducers of differentiation, i.e., dimethylformamide, retinoic acid, sodium butyrate and TGF-beta, distinct patterns of sensitivity and resistance emerged. Nuclear c-myc levels were reduced in all the colon cell phenotypes treated with dimethylformamide or sodium butyrate. Only the well-differentiated human colon tumor cell lines were responsive to transforming growth factor-beta. Only one of the human colon tumor cell lines (GEO) responded to retinoic acid. Increased levels of c-myc protein were found to correlate well with greater growth rates and with poor differentiation class. Similarly, a parallel sensitivity to down-regulation of c-myc levels and attenuation of c-myc induction curves for inducers of differentiation were observed in growth sensitive human colon tumor cell lines.

Butyrates↗
PubMed1991

Mechanisms of resistance to etoposide and teniposide in acquired resistant human colon and lung carcinoma cell lines.

Stable acquired resistance to etoposide (VP-16) or teniposide (VM-26) in HCT116 human colon carcinoma cells and A549 human lung adenocarcinoma cells, was previously obtained by weekly 1-h exposures to either drug (B. H. Long, Natl. Cancer Inst. Monogr., 4: 123-127, 1987). The purpose of this study was to identify possible mechanisms of resistance present in these cells by using human mdr1 and topoisomerase II DNA probes, antibodies to these gene products, and P4 phage unknotting assay for topoisomerase II activities. HCT116(VP)35 cells were 9-, 7-, and 6-fold resistant to VP-16, VM-26, and Adriamycin, respectively, and showed no cross-resistance to colchicine and actinomycin D. These cells had no differences in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels but displayed decreased levels of topoisomerase II mRNA and enzyme activity without any alteration of drug sensitivity displayed by the enzyme. HCT116(VM)34 cells were 5-, 7-, and 21-fold resistant to VP-16, VM-26, and Adriamycin; were cross-resistant to colchicine (7-fold) and actinomycin D (18-fold); and possessed a 9-fold increase in mdr1 mRNA and increased P-glycoprotein without evidence of mdr1 gene amplification. No alterations in topoisomerase II gene or mRNA levels, enzyme activity, or drug sensitivity were observed. A549(VP)28 and A549(VM)28 cells were 8-fold resistant to VP-16 and VM-26 and 3-fold resistant to Adriamycin. Both lines were not cross-resistant to colchicine or actinomycin D but were hypersensitive to cis-platinum. No alterations in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels, but lower topoisomerase II mRNA levels and decreased enzyme activities, were observed. Of the four acquired resistant cell lines, resistance is likely related to elevated mdr1 expression in one line and to decreased topoisomerase II expression in the other three lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗