Acquisition of Resistance to Butyrate Enhances Survival after Stress and Induces Malignancy of Human Colon Carcinoma Cells

Silanes, Isabel López de; Olmo, Nieves; Turnay, Javier; Buitrago, Gonzalo González de; Pérez-Ramos, Pablo; Guzmán-Aránguez, Ana; García-Díez, Marta; Lecona, Emilio; Gorospe, Myriam; Lizarbe, M.A.

doi:10.1158/0008-5472.can-04-0711

Cited by 34 publications

(39 citation statements)

References 33 publications

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“…First, chronic exposure of HCT116/BR cells to butyrate resulted in chemoresistance. Butyrate-resistant BCS-TC2.BR2 human colon adenocarcinoma cells are more tolerant to apoptosis induced by exogenous stimulation (7). Using a cell proliferation assay, we found that HCT116/BR cells had enhanced survivability compared to HCT116/PT cells following treatment with chemotherapeutic agents, such as paclitaxel, doxorubicin, TSA and 5-FU, as well as butyrate.…”

Section: Discussionmentioning

confidence: 86%

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Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

et al. 2016

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Abstract. Butyrate is a short-chain fatty acid produced by the intestinal microflora and it not only induces apoptosis but also inhibits the proliferation of cancer cells. Recently, it has been reported that butyrate may cause resistance in colon cancer cells. Therefore, we investigated the effects of increased resistance to butyrate in HCT116 colon cancer cells. We established HCT116 cells resistant to butyrate (HCT116/ BR) by treating HCT116 parental cells (HCT116/PT) with increasing concentrations of butyrate to a maximum of 1.6 mM for 3 months. The butyrate concentrations that inhibited cell growth by 50% (IC 50 ) were 0.508 and 5.50 mM in HCT116/PT and HCT116/BR cells. The values after treatment with paclitaxel, 5-fluorouracil (5-FU), doxorubicin and trichostatin A (TSA) were 2.42, 2.36, 4.31 and 11.3-fold higher, respectively, in HCT116/BR cells compared with HCT116/PT cells. The protein expression of drug efflux pumps, such as P-glycoprotein (P-gp), breast cancer-resistant protein (BCRP) and the multidrug resistance associated protein 1 (MRP1), did not differ between HCT116/PT and HCT116/BR cells. The expression level of the anti-apoptotic Bcl-xL protein was increased while those of pro-apoptotic Bax and Bim proteins were reduced in HCT116/BR cells. There were no significant differences in cell motility and invasion. This study suggests that exposure of colon cancer cells to butyrate results in development of resistance to butyrate, which may play a role in the acquisition of chemoresistance in colon cancer. IntroductionColon cancer is one of the most common cancers and its prevalence is increasing gradually due to changes in lifestyle (1).Epidemiological studies have attempted to elucidate an association between a high-fiber diet and decreased incidence and progression of colon cancer. Butyrate is a short-chain fatty acid that is naturally produced by the intestinal microflora during dietary fiber fermentation and has been suggested as a target for colon cancer therapy because it inhibits cell proliferation and causes apoptosis in colon cancer cells (2). Butyrate suppresses cell proliferation by causing cell cycle arrest at the G 1 and G 2 phases, which involves cyclin D1 and retinoblastoma (Rb) signaling (3). In addition, butyrate is a histone deacetylase (HDAC) inhibitor, similar to trichostatin A(TSA), and results in apoptosis by increasing the expression of pro-apoptotic proteins, such as Bak, Bad and Bim, and decreasing that of anti-apoptotic proteins, such as Bcl-2 and Bcl-xL (4).Butyrate plays an important role in normal colonocytes as a major energy source and promotes their proliferation (5). However, most cancer cells prefer to utilize glucose as an energy source even under abundant oxygen conditions, so colon cancer cells cannot use butyrate efficiently, which enhances its anticancer effects (6).Recently, it has been reported that butyrate may trigger resistance in colon cancer cells (7). As mentioned above, butyrate is a natural product of dietary fiber fermentation to which colonocytes are c...

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Section: Discussionmentioning

confidence: 86%

“…Recently, it has been reported that butyrate may trigger resistance in colon cancer cells (7). As mentioned above, butyrate is a natural product of dietary fiber fermentation to which colonocytes are consistently exposed.…”

Section: Introductionmentioning

confidence: 97%

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

et al. 2016

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“…An additional goal is to identify the translation-regulatory molecules that function by interacting with MKK4 mRNA, possibly RBPs and/or miRs. Several RBPs that regulate translation and have potential roles in cancer are candidates: HuR is a member of the ELAV family of RBPs (37) and may contribute to malignancy by controlling the expression of specific mRNAs (38). T-cell -restricted intracellular antigen-1 and T-cell -restricted intracellular antigen-1 -related protein are two translational repressors that have roles in development and stress responses (39).…”

Section: Discussionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Kinase 4/c-Jun NH2-Terminal Kinase Kinase 1 Protein Expression Is Subject to Translational Regulation in Prostate Cancer Cell Lines

Robinson¹,

Shalhav²,

Otto³

et al. 2008

Molecular Cancer Research

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Mitogen-activated protein kinase kinase 4/c-Jun NH 2 -terminal kinase kinase 1 (MKK4/JNKK1; hereafter referred to as MKK4) is a dual-specificity kinase with a critical role in regulating the activity of c-Jun NH 2 -terminal kinase and p38 kinases. We identified a novel biological function for MKK4 in the regulation of growth of ovarian and prostate cancer metastases. Clinical correlative studies showed that MKK4 protein levels were reduced in high-grade prostate cancer and prostate and ovarian cancer metastases compared with normal tissue, which prompted investigation into the mechanism(s) responsible for down-regulation of MKK4 in a panel of cancer cell lines. Initial studies found that low levels of MKK4 protein did not correlate with either exon deletion or decreased levels of MKK4 mRNA, suggesting that MKK4 protein levels were regulated posttranscriptionally by either reduced translation or reduced protein stability. Endogenous MKK4 was highly stable and not subject to altered proteolysis. Instead, MKK4 biosynthesis seemed to be regulated by altered translation. In support of this assertion, we found that cytosolic MKK4 mRNA was shifted toward active polysomes in cells with higher levels of MKK4 protein, suggesting that MKK4 mRNA was translated more efficiently in these cells. This study supports a novel mechanism for the regulation of MKK4 protein levels. Further, these findings have potential therapeutic implications for modulating the expression of a signaling kinase involved in the regulation of metastatic growth.

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“…other proteins, resultantly alter the expression of genes, induce apoptosis, arrest cell cycle, and inhibit the angiogenesis and transition of cancer cells [57,68]. However, action modes of HDACi at the level of their molecules [51,92] cannot be satisfactorily explained to cancer patients.…”

Section: Microorganisms That Decompose Polysaccharidementioning

confidence: 99%

Use of Cellulose and Recent Research into Butyrate

Yeo¹,

Choi²,

Cho³

2012

Journal of Life Science

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On earth, there are about 5,400 kinds of mammals, of which about 1,000 kinds are herbivores. Among herbivores, about 250 kinds are known to be ruminants. As for cattle and sheep, which are ruminants, fermentation takes places mainly in their rumen; in contrast, for pigs and men, which are non-ruminants, fermentation takes place mainly in their caecum, colon, and rectum. As for the kind and dominance of rumen microorganisms, Bacteroidetes account for 51% and Firmicutes for 43%. As for the dominance of the large intestine microorganisms in men, Firmicutes account for 65% and Bacteroidetes for 25%. Cell wall components are decomposed by microorganisms, and short chain fatty acids (SCFAs) are generated through fermentation; the ratio of acetate, propionate, and butyrate generate is 60:25:15. Butyrate absorbed through the primary butyrate transporter MCT1 (mono carboxylate transports-1) in the intestines activates such SCFA receptors as GPR43 and GPR41. Butyrate has a strong anti-tumorigenic function. Butyrate is characterized by the fact that it has an effect on many cancer cells, contributes to the coordination of functions in the cells, and induces cancer apoptosis. Butyrate activates caspase but inhibits the activity of HDAC (histone deacetylase), so as to induce apoptosis. In addition, it increases p53 expression, so as to induce cell cycle arrest and apoptosis. Anti-inflammation actions of SCFA include the reduction of IL-8 expression in intestinal epithelial cells, the inhibition of NO synthesis, and the restraint of the activity of NF-kB (nuclear factor kB), so as to suppress the occurrence of cancers caused by inflammation. Butyrate plays an important role in maintaining physiological functions of intestinal mucous membranes and is used as a cure for inflammatory bowel disease (IBD). Digestive organ of ruminant and mono-gastric animals Ruminants are referred to as so because of their rumination or special digestive organ (the stomach), in which cud can be chewed. Ruminants are the most advanced animals of ungulates and the most multiplied and prevalent throughout the world. They have a rumination, which is a very peculiar digestive organ and possibly enables them to have survived poor vegetation conditions, allowing them to flourish greatly. The stomach of all ruminants is divided into four compartments including the rumen, reticulum, omasum, and abomasums (of which rumen and reticulum are involved in rumination and called rumen). Rumination is a process in which food, once swallowed, is emitted back unto the mouth for re-chewing; of feeds returned into reticulum via rumen, those of which over a certain size will be returned again into rumen, accumulated, and regurgitated to the mouth. The regurgitated feeds will be smashed finely between molar teeth and mixed with saliva in the mouth, then returned to rumen for fermentation. Ruminants include cattle, sheep, goats, deer, musk deer, giraffes, and impalas.Pseudo-ruminants have a similar stomach to rumen in which microorganism fermentation takes place, but thei...

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Acquisition of Resistance to Butyrate Enhances Survival after Stress and Induces Malignancy of Human Colon Carcinoma Cells

Cited by 34 publications

References 33 publications

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

Mitogen-Activated Protein Kinase Kinase 4/c-Jun NH2-Terminal Kinase Kinase 1 Protein Expression Is Subject to Translational Regulation in Prostate Cancer Cell Lines

Use of Cellulose and Recent Research into Butyrate

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