SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer

Boulay, Jean-Louis; Mild, Gabriele; Lowy, Adam; Reuter, J; Lagrange, Magali; Terracciano, Luigi; Laffer, U; Herrmann, Richard; Rochlitz, Christoph

doi:10.1038/sj.bjc.6600511

Cited by 77 publications

(69 citation statements)

References 29 publications

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“…One of the proposed mechanisms is through the induction of epithelial-mesenchymal transition by TGF␤ (11). In addition, loss or inactivation of Smad4 has been shown to be a predictive marker for resistance to 5-FU-based chemotherapy in colorectal cancer (46,47). TGF␤ activates non-canonical signaling (i.e.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Such a TGFbdependent increase of the cytotoxic efficiency of drugs may contribute to the efficiency of patient treatment. This mechanism, together with other effects of TGFb, such as growth inhibition, can explain the fact that intact TGFb/Smad signaling in tumor cells correlates with longer survival of patients with breast cancer (Muray et al, 1993;Xie et al, 2002), colorectal (Watanabe et al, 2001;Boulay et al, 2002) and advanced gastric (Xiangming et al, 2001) cancers, renal cell carcinoma (Miyajima et al, 2003) and ovarian cancer (Volodko et al, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage

et al. 2005

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Inactivation of the BRCA1 gene has been found to confer susceptibility to early-onset familial breast and ovarian cancers. BRCA1 regulates DNA repair, chromatin remodeling and affects gene transcription. Transforming growth factor-b (TGFb) is a potent regulator of growth, apoptosis and invasiveness of tumor cells, including breast cancer cells. Here we show that Smad3 which is a component of the TGFb signaling pathway, forms a complex with BRCA1 in vitro and in vivo. The interaction is mediated by the MH1 domain of Smad3 and the Cterminal part of BRCA1. We observed a co-localization of Smad3 and BRCA1 in nuclear complexes. We also found that TGFb1/Smad3 counteracted BRCA1-dependent repair of DNA double-strand breaks in human breast epithelial cells, as evaluated by BRCA1 nuclear foci formation, single-cell gel electrophoresis and cell survival assays. Thus, TGFb1/Smad3 suppresses BRCA1-dependent DNA repair in response to a DNA damaging agent.

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“…13 A scheme of this cascade is provided in our other study. 21 Thus, the 18q21 cluster contains genes encoding all 3 types of SMADs required for regulation of TGF␤ signaling: 2 activators, SMAD2 and SMAD4, and 1 inhibitor, SMAD7.…”

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confidence: 99%

“…15 In addition, we have also defined SMAD4 as a predictive marker for benefit of chemotherapy in patients with CRC, suggesting that integrity of this component of the TGF␤/BMP signaling pathway may also be a condition for efficiency of chemotherapy. 21 We aimed to test whether the deletion of 18q21 genes SMAD2 and SMAD7, plus the DCC gene 3 located nearby, would have a significant influence on the outcome of patients with CRC. To further investigate that issue, we undertook multivariate analyses of copy alterations of the other genes of the 18q21 SMAD gene cluster: SMAD2 and SMAD7.…”

mentioning

confidence: 99%