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Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87.

Huang CC, Wu DW, Lin PL, Lee H - Oncotarget (2015)

Bottom Line: Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy.Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression.In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

ABSTRACT
Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy. Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression. Immunostainings of 190 tumors resected from colorectal cancer patients indicated that PXN expression was positively correlated with Bcl-2, pBcl-2-S87, and MMP2 expression. A positive correlation of pBcl-2-S87 with Bcl-2 and MMP2 was also observed in this study population. Patients with high PXN, Bcl-2, pBcl-2-S87, and MMP2 had poor overall survival (OS) and shorter relapse free survival (RFS). In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients.

No MeSH data available.


Related in: MedlinePlus

The number of lung metastatic tumor nodules in nude mice injected with PXN-overexpressing HT29 cells is strongly reduced by treatment with a Src inhibitor (Dasatinib), ERK inhibitor (AZD6244), MMP2 inhibitor I, or a Bcl-2 antagonist (ABT-199)(A) Example of lungs of mice showing visible metastases at 6 weeks after tail vein injection with the indicated cells. Representative hematoxylin and eosin staining of metastatic lung tumors from each group of mice. (B) Number of metastatic lung tumor nodules in each group of mice. Data are presented as means ± S.E.Ms.
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Figure 3: The number of lung metastatic tumor nodules in nude mice injected with PXN-overexpressing HT29 cells is strongly reduced by treatment with a Src inhibitor (Dasatinib), ERK inhibitor (AZD6244), MMP2 inhibitor I, or a Bcl-2 antagonist (ABT-199)(A) Example of lungs of mice showing visible metastases at 6 weeks after tail vein injection with the indicated cells. Representative hematoxylin and eosin staining of metastatic lung tumors from each group of mice. (B) Number of metastatic lung tumor nodules in each group of mice. Data are presented as means ± S.E.Ms.

Mentions: We next examined whether Src, ERK, Bcl-2, and MMP2 inhibitors or antagonists could inhibit lung tumor nodule formation in nude mice injected with a PXN-overexpressing HT29 stable clone. We first tested the possibility that cell invasiveness mediated by PXN overexpression in HT29 cells could be modulated by Src, ERK or MMP2 inhibitor, and Bcl-2 antagonist. As shown in Figure 2E, Western blotting indicated that pPXN-Y118 expression in a PXN-overexpressing HT29 stable clone was almost completely suppressed by the Src inhibitor Dasatinib, but was unchanged by the ERK inhibitor AZD6244 (Figure 2E). In addition, the expression of pERK, Bcl-2, and MMP2 was almost completely eliminated by both Dasatinib and AZD6244, while the expression of pERK and Bcl-2 was unchanged by treatment with ABT-199 (Figure 2E). Active MMP2 expression was almost completely abolished by MMP2 inhibitor I in the stable clone. The invasion capability of a PXN-overexpressing HT29 stable clone was nearly completely reversed by Dasatinib, AZD6244, ABT-199, and MMP2 inhibitor I when compared with VC cells (Figure 2E), indicating that MMP2 expression induced by PXN overexpression is responsible for cell invasiveness in the HT29 stable clone. In animal model, the lung metastatic tumor nodules in each group of nude mice are shown in Figure 3A. The number of lung metastatic tumor nodules in each group was strongly reduced by treatment with Dasatinib, AZD6244, ABT-199, and MMP2 inhibitor I (Figure 3B). These results clearly indicate that lung tumor metastasis in nude mice may be induced by upregulation of MMP2 due to PXN-mediated stabilization of Bcl-2 protein via activation of the Src/ERK signaling pathway in the PXN-overexpressing HT29 stable clone.


Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87.

Huang CC, Wu DW, Lin PL, Lee H - Oncotarget (2015)

The number of lung metastatic tumor nodules in nude mice injected with PXN-overexpressing HT29 cells is strongly reduced by treatment with a Src inhibitor (Dasatinib), ERK inhibitor (AZD6244), MMP2 inhibitor I, or a Bcl-2 antagonist (ABT-199)(A) Example of lungs of mice showing visible metastases at 6 weeks after tail vein injection with the indicated cells. Representative hematoxylin and eosin staining of metastatic lung tumors from each group of mice. (B) Number of metastatic lung tumor nodules in each group of mice. Data are presented as means ± S.E.Ms.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496177&req=5

Figure 3: The number of lung metastatic tumor nodules in nude mice injected with PXN-overexpressing HT29 cells is strongly reduced by treatment with a Src inhibitor (Dasatinib), ERK inhibitor (AZD6244), MMP2 inhibitor I, or a Bcl-2 antagonist (ABT-199)(A) Example of lungs of mice showing visible metastases at 6 weeks after tail vein injection with the indicated cells. Representative hematoxylin and eosin staining of metastatic lung tumors from each group of mice. (B) Number of metastatic lung tumor nodules in each group of mice. Data are presented as means ± S.E.Ms.
Mentions: We next examined whether Src, ERK, Bcl-2, and MMP2 inhibitors or antagonists could inhibit lung tumor nodule formation in nude mice injected with a PXN-overexpressing HT29 stable clone. We first tested the possibility that cell invasiveness mediated by PXN overexpression in HT29 cells could be modulated by Src, ERK or MMP2 inhibitor, and Bcl-2 antagonist. As shown in Figure 2E, Western blotting indicated that pPXN-Y118 expression in a PXN-overexpressing HT29 stable clone was almost completely suppressed by the Src inhibitor Dasatinib, but was unchanged by the ERK inhibitor AZD6244 (Figure 2E). In addition, the expression of pERK, Bcl-2, and MMP2 was almost completely eliminated by both Dasatinib and AZD6244, while the expression of pERK and Bcl-2 was unchanged by treatment with ABT-199 (Figure 2E). Active MMP2 expression was almost completely abolished by MMP2 inhibitor I in the stable clone. The invasion capability of a PXN-overexpressing HT29 stable clone was nearly completely reversed by Dasatinib, AZD6244, ABT-199, and MMP2 inhibitor I when compared with VC cells (Figure 2E), indicating that MMP2 expression induced by PXN overexpression is responsible for cell invasiveness in the HT29 stable clone. In animal model, the lung metastatic tumor nodules in each group of nude mice are shown in Figure 3A. The number of lung metastatic tumor nodules in each group was strongly reduced by treatment with Dasatinib, AZD6244, ABT-199, and MMP2 inhibitor I (Figure 3B). These results clearly indicate that lung tumor metastasis in nude mice may be induced by upregulation of MMP2 due to PXN-mediated stabilization of Bcl-2 protein via activation of the Src/ERK signaling pathway in the PXN-overexpressing HT29 stable clone.

Bottom Line: Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy.Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression.In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

ABSTRACT
Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy. Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression. Immunostainings of 190 tumors resected from colorectal cancer patients indicated that PXN expression was positively correlated with Bcl-2, pBcl-2-S87, and MMP2 expression. A positive correlation of pBcl-2-S87 with Bcl-2 and MMP2 was also observed in this study population. Patients with high PXN, Bcl-2, pBcl-2-S87, and MMP2 had poor overall survival (OS) and shorter relapse free survival (RFS). In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients.

No MeSH data available.


Related in: MedlinePlus