Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells

Simms, Neka; Rajput, Ashwani; Sharratt, Elizabeth; Ongchin, Melanie; Teggart, Carol A.; Wang, Jing; Brattain, Michael G.

doi:10.1186/1471-2407-12-221

Cited by 16 publications

(26 citation statements)

References 56 publications

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“…One important difference between 5-FU-sensitive and -resistant cells is TGF␤ signaling. Although 5-FU-sensitive RKO and HCT116 cells are defective in TGF␤ signaling because of the mutations in TGF␤ RII (3), 5-FU resistant FET and CBS cells are responsive or partially responsive to TGF␤ signaling, respectively (36,38). This suggests that the TGF␤ signaling pathway may play a role in the 5-FU response.…”

Section: Tgf␤ Signaling Mediates Drugmentioning

confidence: 85%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGF␤ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGF␤ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGF␤ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGF␤/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.Colorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer mortality in the United States. In addition to surgery, treatment for colorectal cancer patients, especially for patients with advanced disease, primarily relies on chemotherapy and radiation therapy. 5 is one of the most commonly used chemotherapeutic agents for colorectal cancer treatment. It induces cell cycle arrest and apoptosis in cancer cells (1). Although adjuvant 5-FU treatment has a good success rate, the high recurrence is still a major hurdle of treating colorectal cancer because of the resistance to chemotherapeutic drugs. Therefore, it is important to understand the mechanisms of drug resistance and identify new targets to increase the effectiveness of chemotherapy in colorectal cancer. TGF␤ plays an important role in cancer development and progression. Upon ligand binding, TGF␤ type II receptor (RII) recruits and activates TGF␤ type I receptor (RI), which then activates Smad2 and Smad3. Activated Smad2 and Smad3 form complexes with Smad4 and translocate to the nucleus, where they regulate gene expression (2). We and others have demonstrated that TGF␤ suppresses tumorigenicity in a variety of cancers, including colorectal cancer, and that loss of TGF␤ signaling leads to malignancy (3-6). Although many studies have shown that TGF␤ promotes metastasis (7), others have demonstrated that TGF␤ suppresses metastasis (8,9). Recently, studi...

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Section: Tgf␤ Signaling Mediates Drugmentioning

confidence: 85%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

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“…CBS cells, moderately metastatic in vivo (20), were used. CBS control and LGR5 knockdown cells were stably transfected with GFP.…”

Section: Resultsmentioning

confidence: 99%

“…The TGFβ axis has been shown to inhibit cell proliferation, induce apoptosis and suppress tumorigenicity in many colon cancer cell lines (17) and in intestinal adenomas (18). Abrogation of TGFβ signaling increases metastasis whereas enhanced TGFβ signaling suppresses metastasis in an orthotopic model of colon cancer (19;20). In genetic mouse models, Smad3 or Smad4 mutation increases malignancy and invasiveness of intestinal tumors of Apc min/+ or knockout mice (21;22), indicating a suppressive role of TGFβ signaling in malignant progression of colon tumors.…”

Section: Introductionmentioning

confidence: 99%

R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis

et al. 2017

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Leucine rich repeat containing G protein-coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel crosstalk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

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“…Using the orthotopic implantation model that we have extensively described in previous studies [13-19, 35, 36], GEO primary colon carcinoma and liver metastasis were obtained as shown in Figure 1A. The protein lysates from the tumors were compared for their global protein expression by 2D-DIGE (performed at Applied Biomics, Inc).…”

Section: Resultsmentioning

confidence: 99%

Ezrin expression and cell survival regulation in colorectal cancer

Leiphrakpam

Rajput

Mathiesen

et al. 2014

Cellular Signalling

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Colorectal cancer (CRC) is the second largest cause of cancer deaths in the United States. A key barrier that prevents better outcomes for this type of cancer as well as other solid tumors is the lack of effective therapies against the metastatic disease. Thus there is an urgent need to fill this gap in cancer therapy. We utilized a 2D-DIGE proteomics approach to identify and characterize proteins that are differentially regulated between primary colon tumor and liver metastatic deposits of the IGF1R-dependent GEO human CRC xenograft, orthotopically implanted in athymic nude mice that may serve as potential therapeutic targets against CRC metastasis. We observed increased expression of ezrin in liver metastasis in comparison to the primary colonic tumor. Increased ezrin expression was further confirmed by western blot and microarray analyses. Ezrin, a cytoskeletal protein belonging to Ezrin-Radixin-Moesin (ERM) family plays important roles in cell motility, invasion and metastasis. However, its exact function in colorectal cancer is not well characterized. Establishment of advanced GEO cell lines with enhanced liver-metastasizing ability showed a significant increase in ezrin expression in liver metastasis. Increased phosphorylation of ezrin at the T567 site (termed here as p-ezrin T567) was observed in liver metastasis. IHC studies of human CRC patient specimens showed an increased expression of p-ezrin T567 in liver metastasis compared to the primary tumors of the same patient. Ezrin modulation by siRNA, inhibitors and T567A/D point mutations significantly downregulated inhibitors of apoptosis (IAP) proteins XIAP and survivin that have been linked to increased aberrant cell survival and metastasis and increased cell death. Inhibition of the IGF1R signaling pathway by humanized recombinant IGF1R monoclonal antibody MK-0646 in athymic mouse subcutaneous xenografts resulted in inhibition of p-ezrin T567 indicating ezrin signaling is downstream of the IGF1R signaling pathway. We identified increased expression of p-ezrin T567 in CRC liver metastasis in both orthotopically implanted GEO tumors as well as human patient specimens. We report for the first time that p-ezrin T567 is downstream of the IGF1R signaling and demonstrate that ezrin regulates cell survival through survivin/XIAP modulation.

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Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells

Cited by 16 publications

References 56 publications

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis

Ezrin expression and cell survival regulation in colorectal cancer

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