Prognostic Value of ERCC1, Thymidylate Synthase, and Glutathione S-Transferase π for 5-FU/Oxaliplatin Chemotherapy in Advanced Colorectal Cancer

Kim, Sung-Hyun; Kwon, Hyuk‐Chan; Oh, Sung Yong; Lee, Dong Mee; Lee, Suee; Lee, Jong Hoon; Roh, Mee‐Sook; Kim, Dae‐Cheol; Park, Ki-Jae; Choi, Hong-Jo; Kim, Hyojin

doi:10.1097/coc.0b013e31817be58e

Cited by 87 publications

(61 citation statements)

References 27 publications

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“…To determine whether knockdown of PDK4 sensitizes colon cancer cells to other chemotherapeutic drugs, HCT116 cells were treated with oxaliplatin, an alkylating agent commonly used in combination with 5-FU for treating advanced colon cancer (30,31). Similar to 5-FU, oxaliplatin treatment induced more apoptosis in PDK4 knockdown cells than in control cells, as shown by DNA fragmentation assays and PARP cleavage (Fig.…”

Section: Genetic or Pharmacological Inhibition Of Pdk4 Sensitizes Colmentioning

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: Genetic or Pharmacological Inhibition Of Pdk4 Sensitizes Colmentioning

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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“…Later studies confirmed the predictive role of ERCC1 in NSCLC [12,37] and other types of cancer, such as colorectal cancer [17], gastric carcinoma [16,[38][39], and esophageal cancer [40]. Our study showed that patients with lower expression of ERCC1 had relatively higher DCR than patients with higher gene expression when they received platinum-based chemotherapy, which is consistent with previous studies.…”

Section: Discussionsupporting

confidence: 82%

Individualized treatment of NSCLC: From research to clinical practice

Zd²,

Lm³

et al. 2013

neo

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The exact clinical significance of EGFR mutation status in NSCLC at the time of initial diagnosis remains disputable. The gene expression module in NSCLC for chemotherapy outcome prediction needs to be developed. We analyzed 56 patients with NSCLC received chemotherapy either with (n=20) or without EGFR-TKIs (n=36) between 2008 and 2012 in China. EGFR mutation test and gene expression profiling were performed in samples obtained before medication treatment by liquidchip platform. Significant association (P = 0.028) was seen between EGFR mutation status before first-line chemotherapy and EGFR-TKIs treatment outcomes, which even can be found from the status before second-or third-line treatment. A 14-gene expression profiling had been studied. Patients with low mRNA expression of ERCC1 or TYMS preferred higher DCR to cisplatin and pemetrexed than those with high expression (P = 0.39 and P = 0.11). Highly co-expression of TUBB3 and STMN1 gene has associated with the resistance to antimicrotubule drugs (P = 0.03). Our data suggest the EGFR mutations status, even at the time of initial diagnosis, is predictive of outcomes of TKIs treatment after chemotherapy. The mRNA expression profiling investigated in this study has a predictive value in NSCLC treatment, but further research with expanded samples is still required.

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“…The similar mete-analysis was performed by Chen and the same conclusion was gained (Chen et al, 2010). In addition, many papers evaluated the relation between ERCC1 status and response to chemotherapy have been reported in various human cancers including Colorectal Cancer, bladder cancer, cervical cancer, Head and Neck Cancer, and most of studies showed ERCC1 expression was a predictor of response to chemotherapy (Handra-Luca et al, 2007;Braun et al, 2008;Kim et al, 2009;Ishibashi et al, 2010;Kim et al, 2010;Hayes et al, 2011;Kawashima et al, 2011;Park et al, 2011;Sun et al, 2012). In 2008, Lin et al performed a cohort study to evaluate the difference of ERCC1 protein expression levels between 36 sensitive cases and 27 resistant cases of serous ovarian cancer receiving neoadjuvant chemotherapy and demonstrated that ERCC1 protein expression levels in resistance group of serous ovarian cancer were significantly higher than those of sensitivity group, and Lin et al's study was in accordance with our meta-analysis (Lin et al, 2008).…”

Section: Discussionmentioning

confidence: 61%

Meta-analysis of Excision Repair Cross-complementation Group 1 (ERCC1) Association with Response to Platinum-based Chemotherapy in Ovarian Cancer

Ren²,

Xie³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Recent studies suggested that the ovarian cancers with negative excision repair cross-complementation group 1 enzyme (ERCC1) expression have a better response to platinum-based chemotherapy than those with positive ERCC1 expression. The objective of this study was to evaluate whether ERCC1 expression is associated with response to platinum-based chemotherapy in ovarian cancers. MEDLINE, PubMed, Web of Science and CNKI databases were used for searching studies relating to ERCC1 protein expression and response to platinum-based chemotherapy in ovarian cancers. Statistical analysis was based on the method for a fixed effects meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals for ERCC1 protein expression and response to platinumbased chemotherapy were generated. Publication bias was investigated with Begg's test. Five studies involving 306 patients with ovarian cancer were included. Compared to patients with positive ERCC1 expression, those with negative ERCC1 expression had a better response to platinum-based chemotherapy. The pooled OR was 5.264 (95% CI: 2.928 -9.464, P < 0.001) and publication bias was not found (P = 0.904). The result was similar in both in Asians and Caucasians (P < 0.001 and P = 0.028, respectively). ERCC1 protein expression status is significantly associated with response to platinum-based chemotherapy in ovarian cancers.

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Prognostic Value of ERCC1, Thymidylate Synthase, and Glutathione S-Transferase π for 5-FU/Oxaliplatin Chemotherapy in Advanced Colorectal Cancer

Abstract: Immunohistochemical study of ERCC1 and TS may be useful for the prediction of clinical outcome in patients with advanced colorectal cancer treated with 5-FU and oxaliplatin.

Cited by 87 publications

References 27 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

Individualized treatment of NSCLC: From research to clinical practice

Meta-analysis of Excision Repair Cross-complementation Group 1 (ERCC1) Association with Response to Platinum-based Chemotherapy in Ovarian Cancer

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