Involvement of PI3K/Akt Signaling Pathway in Hepatocyte Growth Factor–Induced Migration of Uveal Melanoma Cells

Ye, Mao; Hu, Dan‐Ning; Tu, Lili; Zhou, Xiangtian; Liu, Fan; Wen, Bin; Wu, Wencan; Lin, Yi Wen; Zhou, Zhongxin; Qu, Jia

doi:10.1167/iovs.07-0975

Cited by 94 publications

(88 citation statements)

References 31 publications

(25 reference statements)

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“…Previous studies have suggested the important role of c-Met overexpression in uveal melanoma metastasis and the regulation of its ligand, HGF, in determining tumor dissemination (32). Furthermore, c-Met-induced PI3K/AKT signaling has been linked to enhance cell migration of uveal melanomas (33). As we confirmed that c-Met plays a significant role in uveal melanoma cell migration, and that HGF is in fact expressed and secreted by these cells, a metastatic model was developed to demonstrate the inhibition of metastasis by crizotinib.…”

Section: Discussionsupporting

confidence: 71%

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Surriga

Rajasekhar

Ambrosini

et al. 2013

Molecular Cancer Therapeutics

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Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung. Crizotinib, an inhibitor of c-Met, anaplastic lymphoma kinase (ALK), and ROS1, inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue. Consequently, migration of uveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation. This effect on cell migration could be recapitulated with siRNA specific to c-Met but not to ALK or ROS1. Therefore, we developed a uveal melanoma metastatic mouse model with EGFPluciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis. In this model, there was development of melanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation. When mice were treated with crizotinib starting 1 week after the transplantation, we observed a significant reduction in the development of metastases as compared with untreated control sets. These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming, suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.

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Section: Discussionsupporting

confidence: 71%

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Surriga

Rajasekhar

Ambrosini

et al. 2013

Molecular Cancer Therapeutics

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“…For example, Akt converted radial growth to vertical growth in melanoma cells (10). Recently, PI3K-Akt signaling has been reported to be involved in the hepatocyte growth factorinduced migration of uveal melanoma cells (11).…”

Section: Discussionmentioning

confidence: 99%

Proteolipid protein 2 is associated with melanoma metastasis

Sonoda¹

2009

Oncol Rep

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Abstract. The metastasis of malignant tumor cells from the primary tumor to distant sites in the body is a complex process. To identify genes that may be essential for metastasis, we established poorly metastatic mouse melanoma cells, namely Y925F-mutated FAK-transfected cells (Y925F cells), from the highly metastatic mouse melanoma cell line B16F10, and performed expression analyses. The expression of phospholipid protein 2 (PLP2) was markedly down-regulated in the Y925F cells. To elucidate the function of PLP2, we established melanoma cells overexpressing PLP2. We found that PLP2 enhanced proliferation, adhesion, invasion, and MMP-2 secretion in vitro, and tumor metastasis in vivo. These results suggest that PLP2 aids metastasis. Furthermore, we showed that PLP2 binds specifically to PI3K, thus activating Akt.

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“…In uveal melanoma, PI3K pathway downregulates the cell adhesion molecules E-cadherin and β-catenin, thus attenuating cell-cell adhesion and promoting the enhanced motility and migration typically seen in these cancer cells. 159 Also, in MDA-MB-435 breast carcinoma cells, upregulation of PI3K via α6β4 integrin signaling leads to increased invasion that is Rac dependent but MAPK and p70S6K independent.…”

Section: Ras-pi3k In Metastasis Formationmentioning

confidence: 99%

RAS Interaction with PI3K: More Than Just Another Effector Pathway

2011

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RAS proteins are small GTPases known for their involvement in oncogenesis: around 25% of human tumors present mutations in a member of this family. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate many cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. However, it is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRASinduced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. Many PI3K inhibitors have been developed that are now in clinical trials. However, it is a complex pathway with many feedback loops, and interactions with other pathways make the results of its inhibition hard to predict. Combined therapy with another RAS-regulated pathway such as RAF/MEK/ ERK may be the most effective way to treat cancer, at least in animal models mimicking the human disease. In this review, we will summarize current knowledge about how RAS regulates one of its best-known effectors, PI3K.

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Involvement of PI3K/Akt Signaling Pathway in Hepatocyte Growth Factor–Induced Migration of Uveal Melanoma Cells

Abstract: Data from this study directly linked the central PI3K/Akt pathway to uveal melanoma migration and pointed to new avenues for therapeutic intervention in hepatic metastasis.

Cited by 94 publications

References 31 publications

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Crizotinib, a c-Met Inhibitor, Prevents Metastasis in a Metastatic Uveal Melanoma Model

Proteolipid protein 2 is associated with melanoma metastasis

RAS Interaction with PI3K: More Than Just Another Effector Pathway

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