Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression

Wu, De Wei; Wu, Tzu Chin; Wu, Jialun; Cheng, Ya‐Wen; Chen, Yen-Chou; Lee, M. C.; Chen, C. Y.; Lee, Huei

doi:10.1038/onc.2013.389

Cited by 64 publications

(66 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, Bcl-2 expression is the key step to protect cells from apoptosis in melanoma. It has a crucial role in chemoresistance in various human cancers (22,23). The present study detected expression of Bcl-2 at 24 h after treatment with the inhibitors.…”

Section: Discussionsupporting

confidence: 49%

Effects of nuclear factor-κB and ERK signaling transduction pathway inhibitors on human melanoma cell proliferation in vitro

et al. 2015

View full text Add to dashboard Cite

Abstract. The present study aimed to investigate the effects of blocking nuclear factor (NF)-κB and/or extracellular signal-regulated kinase (ERK) signaling pathways on proliferation and apoptosis of melanoma cells in vitro. A375 Human melanoma cells were treated with U0126 (ERK signaling pathway inhibitor) and BMS-345541 (NF-κB inhibitor), alone or in combination. At 12, 24 and 48 h after treatment, cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle progression and apoptosis were evaluated by flow cytometry, and Bcl-2 protein content was determined by western blot analysis. BMS-345541 and U0126 significantly inhibited A375 cell proliferation in a dose-and time-dependent manner (P<0.01). The rate of proliferation inhibition at 24 h was 35.41±1.38% for BMS-345541 alone, 30.64±2.86% for U0126 alone, and 77.27±2.70% for BMS-345541 and U0126 in combination. The difference between combination and single treatment was significantly different (P<0.01). The proportion of cells in S phase was 14.20, 18.40 and 22.64% following treatment with BMS-345541, U0126, and BMS-345541 and U0126 in combination, respectively; these values were all significantly reduced compared with the untreated control group (P<0.01). The apoptosis rate was 24.98±1.03% in the BMS-345541 group, 13.96±0.96% in the U0126 group and 38.91±1.46% in the combination group; all significantly increased compared with the control group (P<0.01). Bcl-2 protein content in A375 cells was significantly increased following treatment with BMS-345541 and U0126, alone or in combination, when compared with the untreated control group (P<0.01). Therefore, NF-κB and ERK signaling pathway inhibitors may serve as potential therapeutic targets for melanoma.

show abstract

Section: Discussionsupporting

confidence: 49%

Effects of nuclear factor-κB and ERK signaling transduction pathway inhibitors on human melanoma cell proliferation in vitro

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that PXN plays an important role in regulating tumor cell proliferation and mediating signal transduction of epidermal growth factor (EGF) (2,(10)(11)(12). Various scholars have also demonstrated that PXN leads to resistance to drugs by inhibiting the apoptosis of cancer cells in non-small cell lung cancer (17). In the present study, following treatment of cetuximab in SW480 and Caco-2 cells for a period of time, the expression of PXN in SW480 cells declined at first, and then gradually increased and finally stabilized, which was consistent with the proliferation rate.…”

Section: Discussionmentioning

confidence: 99%

“…As for the mechanisms, it is assumed that PXN plays a role in regulating the signaling pathway in the downstream of KRAS. As described in the Introduction, activation of the ERK signaling pathway requires the participation and mediation of PXN in prostate cancer and non-small cell lung cancer (10,17 (11). Several studies have demonstrated that Erk always gives a positive feedback on PXN and plays an important part in the activitation of PXN and interaction between FAK and PXN (11,22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Sen et al discovered that after knockdown of the PXN gene in prostate cancer cells, the phosphorylation level of extracellular regulated-protein kinase (Erk) significantly decreased in the downstream of mitogen-activated protein kinase (MAPK) pathway, which proves that activation of the Erk signaling pathway requires PXN involvement and PXN is necessary for the proliferation of prostate cancer cells (11). In a study of non-small cell lung cancer (NSCLC), Wu et al found that activation of Erk requires mediation of PXN and further confirms that expression of the B-cell leukemia/lymphoma-2 (Bcl-2) gene is regulated by PXN through activation of Erk, while high expression of the Bcl-2 gene inhibits cancer cell apoptosis, causing resistance to chemotherapeutic drugs in lung cancer patients (17). Despite these previous studies, whether PXN overexpression is one of the reasons for resistance to cetuximab and how PXN affects the MAPK pathway in colorectal cancer cells remain unknown.…”

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Wang

Zhang

et al. 2015

Oncology Reports

View full text Add to dashboard Cite

Abstract. Paxillin (PXN) encodes a 68-kDa focal adhesionassociated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer.

show abstract

“…Total RNA extraction and reverse transcriptase reaction were described previously. 8 The following primer sequences were used for amplification of the Bcl-2 gene: the forward primer, 5′-CTGTGGATGACTGAGTACC-3′ and the reverse primer, 5′-CAGCCAGG AGAAATCAAAC-3′.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

Huang

Chang

et al. 2014

Cell Death Differ

Self Cite

View full text Add to dashboard Cite

5-Fluorouracil (5-FU) is chemotherapeutic agent widely used for the treatment of colorectal cancer. Unfortunately, advanced colorectal cancer is often resistance to such chemotherapy and poor outcome. An adaptor protein paxillin (PXN) is phosphorylated at Y31/Y118 (pPXN-Y31/Y118) by Src contributes to cell mobility and Ser (S)272 of PXN in LD4 domain is important to the interaction between PXN and Bcl-2. We thus hypothesized that pPXN-Y31/Y118 may be required for Bcl-2 protein stability via PXN interacting with Bcl-2 to confer 5-FU resistance in colorectal cancer. Mechanistically, pPXN-S272 is phosphorylated through pPXN-Y31/Y118-mediated p21 protein-activated kinase 1 (PAK1) activation and pPXN-S272 is required for PXN to interact with Bcl-2. The interaction between PXN and Bcl-2 is essential for Bcl-2 protein stability through phosphorylation of Bcl-2 at S87 (pBcl-2-S87) by pPXN-Y31/ Y118-mediated ERK activation. An increase in Bcl-2 expression by PXN is responsible for resistance to 5-FU. The resistance to 5-FU can be abolished by inhibitor of Src and PAK1 or Bcl-2 antagonist in cell and animal models. Among patients, Bcl-2 expression is positively correlated with expression of PXN and pPXN-S272, respectively. Patients with high PXN/high Bcl-2 or high pPXN-S272/high Bcl-2 tumors are commonly to have an unfavorable response to 5-FU-based chemotherapy, compared with patients who have high PXN, high pPXN-S272 or high Bcl-2 tumors alone. Therefore, we suggest that Src, PAK1 or Bcl-2 inhibitor may potentially overcome the resistance of 5-FU-based chemotherapy and consequently to improve outcomes in patients with PXN/Bcl-2 and pPXN-S272/Bcl-2-positive tumors. Cell Death and Differentiation (2015) 22, 779-789; doi:10.1038/cdd.2014.170; published online 17 October 2014The incidence of colorectal cancer has markedly increased over the past two decades and became the third leading cancer death in Taiwan.1,2 Patients with colorectal cancer commonly receive 5-fluorouracil (5-FU)-based chemotherapy after surgical resection. 3 The 5-year survival of Dukes B patients is approximately 75%, indicating that~25% of Dukes B patients may potentially benefit from adjuvant chemotherapy. 4 However, the response rate of advancedstage patients to 5-FU-based chemotherapy was only 10-15%. 5 Therefore, there is an urgent need to establish therapeutic biomarkers and available clinical approaches to improve the response of colorectal patients who received 5-FU-based chemotherapy.Paxillin (PXN) has been shown to promote tumor aggressiveness, including that of colorectal cancer. 6 A recent report indicated that PXN may promote cell proliferation in SW480 colon cancer cells and PXN expression was associated with overall survival (OS) but not related with Bcl-2 in colorectal cancer patients. 7 Our previous report indicated that phosphorylation of PXN at Y31/Y118 (pPXN-Y31/Y118) by Src signaling pathway increased Bcl-2 expression at a transcriptional level in lung cancer cells via ERK activation.8 Surprisingly, our preliminary data showed that ...

show abstract

Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression

Cited by 64 publications

References 43 publications

Effects of nuclear factor-κB and ERK signaling transduction pathway inhibitors on human melanoma cell proliferation in vitro

Effects of nuclear factor-κB and ERK signaling transduction pathway inhibitors on human melanoma cell proliferation in vitro

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

Contact Info

Product

Resources

About