Expression of retinoid-responsive genes occurs in colorectal carcinoma-derived cells irrespective of the presence of resistance to all-trans retinoic acid

Waliszewski, Przemysław; Waliszewska, Miroslawa; M.D., M.R.C.P. Sanjeev Gupta; Milsom, Jeffrey W.; Hurst, Robert E.

doi:10.1002/(sici)1096-9098(199711)66:3<156::aid-jso2>3.0.co;2-b

Cited by 9 publications

(11 citation statements)

References 41 publications

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“…3B-D). The lack of CAT activity in cells treated with ATRA confirms the inability of these cells to respond to ATRA via RAR/ RARE-mediated mechanisms as described previously (11,17,18 (Fig. 2) and the lack of CAT activity in SW620 cells when treated with retinol both confirms the metabolism data and shows that an RAR-activating metabolite of retinol is either not present or is incapable of activating RAR/ RARE-mediated gene transcription.…”

Section: Resultssupporting

confidence: 88%

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Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Park

Dillard²,

Williams³

et al. 2005

Cancer Research

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Retinol (vitamin A) is thought to exert its effects through the actions of its metabolite, all-trans-retinoic acid (ATRA), on gene transcription mediated by retinoic acid receptors (RAR) and retinoic acid response elements (RARE). However, retinoic acid resistance limits the chemotherapeutic potential of ATRA. We examined the ability of retinol to inhibit the growth of ATRA-sensitive (HCT-15) and ATRA-resistant (HCT-116, SW620, and WiDR) human colon cancer cell lines. Retinol inhibited cell growth in a dose-responsive manner. Retinol was not metabolized to ATRA or any bioactive retinoid in two of the cell lines examined. HCT-116 and WiDR cells converted a small amount of retinol to ATRA; however, this amount of ATRA was unable to inhibit cell growth. To show that retinol was not inducing RARE-mediated transcription, each cell line was transfected with pRARE-chloramphenicol acetyltransferase (CAT) and treated with ATRA and retinol. Although treatment with ATRA increased CAT activity 5-fold in ATRAsensitive cells, retinol treatment did not increase CAT activity in any cell line examined. To show that growth inhibition due to retinol was ATRA, RAR, and RARE independent, a pan-RAR antagonist was used to block RAR signaling. Retinol-induced growth inhibition was not alleviated by the RAR antagonist in any cell line, but the antagonist alleviated ATRA-induced growth inhibition of HCT-15 cells. Retinol did not induce apoptosis, differentiation or necrosis, but affected cell cycle progression. Our data show that retinol acts through a novel, RAR-independent mechanism to inhibit colon cancer cell growth. (Cancer Res 2005; 65(21): 9923-33)

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Section: Resultssupporting

confidence: 88%

“…The ability of retinol to inhibit cell growth was examined in three ATRA-resistant human colon cancer cell lines HCT-116 (17), SW620 (18), and WiDR (11). An ATRAsensitive cell line, HCT-15, was chosen to serve as a positive control for the inhibitory effects of ATRA on colon cancer cell growth (19).…”

Section: Resultsmentioning

confidence: 99%

Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Park

Dillard²,

Williams³

et al. 2005

Cancer Research

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“…All these cell lines respond to retinoic acid by decreased proliferation and increased activation of retinoic acid-sensitive genes and RARE reporters (14,15). However, not all colon cancer cells respond to retinoic acid by decreasing growth even though RA-treatment continues to activate RARE reporters in these cells (2). We wanted to investigate whether the failure of these cells to respond to RA by decreased proliferation was associated with loss of trans-repression of ␤-catenin signaling.…”

Section: Differential Response Of ␤-Catenin/tcf and Retinoic Acidrespmentioning

confidence: 99%

“…In some cases, resistance is because of a defect in particular nuclear receptor isoforms. However, some cells, which are not growth-inhibited by vitamin A, express normal retinoic acid receptors (RARs) 1 /RXRs and retain the ability to up-regulate retinoid-sensitive genes (2). These data indicate that other molecules such as components of the cadherin/␤-catenin-based signaling and adhesion system may also need for retinoic acid to exert its anti-proliferative effects (3,4).…”

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confidence: 99%

Trans-repression of β-Catenin Activity by Nuclear Receptors

Shah

Hecht

Pestell

et al. 2003

Journal of Biological Chemistry

111

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The signaling/oncogenic activity of ␤-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with ␤-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of ␤-catenin signaling by nuclear receptors and their ligands.By definition, the term chemoprevention refers to the treatment of individuals with premalignant lesions, individuals who are predisposed to the development of malignant lesions, and individuals early in the process of carcinogenesis, with the intention of preventing the later stages of carcinogenesis from developing (1). Although chemopreventative agents such as vitamins A and D are often effective in this context there is no de facto reason to assume that the same treatment would not be effective in more advanced stages of carcinogenesis. Nevertheless, this is often not the case because many advanced cancers in vivo and de-differentiated carcinoma cells in vitro are refractory to the anti-tumor, growth inhibitory activities of vitamins A and D. Thus, not only do more malignant tumors and cells have defects in the expression and function of several molecules characteristic of differentiated epithelial cells; they are also less responsive to differentiating agents. An obvious question arises from this realization; what are the molecular mechanisms that underlie resistance to vitamins A and D? In some cases, resistance is because of a defect in particular nuclear receptor isoforms. However, some cells, which are not growth-inhibited by vitamin A, express normal retinoic acid receptors (RARs) 1 /RXRs and retain the ability to up-regulate retinoid-sensitive genes (2). These data indicate that other molecules such as components of the cadherin/␤-catenin-based signaling and adhesion system may also need for retinoic acid to exert its anti-proliferative effects (3, 4).Recently, several studies show that the signaling/oncogenic activity of ␤-catenin is trans-repressed by the activation of nuclear receptors such as RAR, vitamin D receptor (VDR), and androgen receptors (AR) (3, 5). In addition to its role in cell-cell adhesion ␤-catenin acts as a co-activator for the TCF/lymphoid enhancer factor (LEF) family of transcription factors. Although it is possible that all of these receptors directly interact with ␤-catenin and sequester it away from TCF, it is not known if this is the mechanism of trans-repression. Nuclear receptors also trans-repress AP-1, serum response factor (SRF), and NFB activity by a mechanism likely involving interaction with a common pool of co-activators rather than a direct interaction with transcription factors (6 -8). On the other hand, in contrast to AP-1, high levels of ␤-catenin mark...

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“…Also, two or more phenotypic traits may be ascribed to the same gene. Indeed, the same or very similar genotypes may produce distinct phenotypes and, inversely, the same or very similar phenotypes may be associated with distinct patterns of gene expression [3,[22][23][24][25][26]. For example, a relatively homogeneous population of normal epithelial cells expressing the same or very similar set of genes undergoes metaplastic transformation when exposed to the conditions existing in the surgical conduits, fistulas, or during chronic inflammation [27,28].…”

Section: The Genotype/phenotype Relationshipmentioning

confidence: 99%

On the holistic approach in cellular and cancer biology: Nonlinearity, complexity, and quasi-determinism of the dynamic cellular network

Waliszewski

Molski²,

Konarski³

1998

J. Surg. Oncol.

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A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype—two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross‐interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controled in dispersed rather than centralized manner), and quasi‐determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self‐organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context. J. Surg. Oncol. 1998;68:70–78. © 1998 Wiley‐Liss, Inc.

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Expression of retinoid-responsive genes occurs in colorectal carcinoma-derived cells irrespective of the presence of resistance to all-trans retinoic acid

Cited by 9 publications

References 41 publications

Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Trans-repression of β-Catenin Activity by Nuclear Receptors

On the holistic approach in cellular and cancer biology: Nonlinearity, complexity, and quasi-determinism of the dynamic cellular network

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