Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells

Kim, Jin Ah; Park, Ki‐Sook; Kim, Ha Il; Oh, Seung Keun; Ahn, Yong-Ho; Oh, Jisun; Choi, Kang Yell

doi:10.1016/s0304-3835(01)00869-2

Cited by 29 publications

(30 citation statements)

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“…Besides, a study reported that troglitazone, the parent molecule of D2-TGZ, activated the ERK pathway and induced p21 Cip/WAF1 in the colorectal cancer cell lines HCT15 and HT29 with a dose of 200 mM in 10% FBS-conditions, whereas 20 mM of TGZ were enough to induce these effects in 1% FBSconditions. 27 Moreover, another study showed that a 7-fold increase in the IC 50 of the antitumor drug Sorafenib (BAY 43-9006, Nexavar) was necessary to inhibit ERK 1/2 phosphorylation in MDA-MB-231 cells in presence of serum, compared to a low protein containing medium (0.1% Bovine Serum Albumin and 0% FCS-containing medium). 28 So, serum starvation enhances the action of D2-TGZ and of other antiproliferative compounds in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

et al. 2016

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We have previously shown that D2-Troglitazone (D2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of D2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with D2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC 50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to D2-TGZ than MDA-MB-231 cells. D2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, D2-TGZ induced a G 0 /G 1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G 1 phase. Thus, in high serum conditions, D2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.

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Section: Discussionmentioning

confidence: 99%

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

et al. 2016

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“…p21 Cip/W AF1 activation was identified as an important marker for anti-proliferation and that related with strong and prolonged ERK activation (Sewing et al, 1997;Woods et al, 1997;Kim et al, 2002;. However, it is not clear whether p21 Cip/W AF1 activation is a required factor or just one of the indicators for anti-proliferation caused by extracellular stimuli that induce prolonged ERK activation.…”

Section: R Esults and Discussionmentioning

confidence: 99%

“…The ERK pathway is involved in growth arrest (Liu et al, 1996;Sewing et al, 1997;Woods et al, 1997;Mahyar-Roemer and Roemer, 2001;Park et al, 2002;Boucher et al, 2004) as well as its well known function of growth stimulation (Blenis, 1993;Chang et al, 2003). Activation of p21 Cip/W AF1 , represented by induction and nuclear localization, is an important marker for anti-proliferation and growth arrest that occurs by prolonged activation of the ERK pathway (Nakano et al, 1997;Archer et al, 1998;Kim et al, 2002;Park et al, 2002;Eum et al, 2003). On the other hand, p21 Cip/WAF1 was not induced by the transient and weak ERK activation that is associated with proliferation (Sewing et al, 1997;Woods et al, 1997;Park et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…The differential activation of ERK that is related to different growth behaviors relies on signaling intensity and the serum concentration . Induction of p21 Cip/W AF1 is an important indicator for anti-proliferation in colorectal cancer cells (Nakano et al, 1997;Archer et al, 1998;Kim et al, 2002;Park et al, 2002). Percentages of cells incorporating BrdU w ere significantly reduced by zinc or TRO inducing p21 Cip/W AF1 Park et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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p21Cip/WAF1 activation is an important factor for the ERK pathway dependent anti-proliferation of colorectal cancer cells

Park

Jeon²,

Oh³

et al. 2004

Exp Mol Med

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“…This happens because the biologic responses are actually mediated by a myriad of signaling cascades downstream of MAPK. Indeed, epidermal growth factor-induced differentiation of pheochromocytoma cells (30) and troglitazone-induced antiproliferative effect in colon cancer cells (31) were previously shown to occur by transient ERK activation that lasted only tens of minutes. Nonetheless, further investigation will be required to clarify the roles of AMPK and MAPK in troglitazone-stimulated glycolysis of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Troglitazone Stimulates Cancer Cell Uptake of ¹⁸F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction

et al. 2015

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We evaluated how troglitazone influences cancer cell glucose metabolism and uptake of 18 F-FDG, and we investigated its molecular mechanism and relation to the drug's anticancer effect. Methods: Human T47D breast and HCT116 colon cancer cells that had been treated with troglitazone were measured for 18 F-FDG uptake, lactate release, oxygen consumption rate, mitochondrial membrane potential, and intracellular reactive oxygen species. Viable cell content was measured by sulforhodamine-B assays. Results: Treatment with 20 μM troglitazone for 1 h acutely increased 18 F-FDG uptake in multiple breast cancer cell lines, whereas HCT116 cells showed a delayed reaction. In T47D cells, the response occurred in a dose-dependent (threefold increase by 40 μΜ) manner independent of peroxisome proliferator-activated receptor-γ and was accompanied by a twofold increase of lactate production, consistent with enhanced glycolytic flux. Troglitazone-treated cells showed severe reductions of the oxygen consumption rate, indicating suppression of mitochondrial respiration, which was accompanied by significantly decreased mitochondrial membrane potential and increased concentration of reactive oxygen species. Troglitazone dose-dependently reduced T47D and HCT116 cell content, which was significantly potentiated by restriction of glucose availability. In T47D cells, cell reduction closely correlated with the magnitude of increase in relative 18 F-FDG uptake (r 5 0.821, P 5 0.001). Conclusion: Troglitazone stimulates cancer cell uptake of 18 F-FDG through a shift of metabolism toward glycolytic flux, likely as an adaptive response to impaired mitochondrial oxidative respiration.

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Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells

Cited by 29 publications

References 24 publications

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

p21Cip/WAF1 activation is an important factor for the ERK pathway dependent anti-proliferation of colorectal cancer cells

Troglitazone Stimulates Cancer Cell Uptake of ¹⁸F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction

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Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells

Cited by 29 publications

References 24 publications

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

p21Cip/WAF1 activation is an important factor for the ERK pathway dependent anti-proliferation of colorectal cancer cells

Troglitazone Stimulates Cancer Cell Uptake of 18F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction

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Troglitazone Stimulates Cancer Cell Uptake of ¹⁸F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction