Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis

Chen, Feng; Wee, Jonathan Wei Kiat; Chen, Huizhi; Ong, Lin Seng; Qu, Jing; Tan, Hui-Foon; Tan, Suet-Mien

doi:10.1080/19336918.2016.1243645

Cited by 13 publications

(13 citation statements)

References 57 publications

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“…For Kindlin-2, increased levels were reported to enhance tumor invasion and poor prognosis in breast, bladder, pancreas, stomach cancers and malignant mesothelioma, whereas they correlated with reduced tumor invasion and metastasis in colorectal and serous epithelial ovarian cancers [ 14 , 18 – 23 ]. Moreover, recent studies provided conflicting results suggesting either a tumor suppressor or a tumor promoting activity of Kindlin-3 in breast cancer and melanomas [ 14 , 24 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Distinct expression profiles and functions of Kindlins in breast cancer

Azorin

Bonin

Moukachar

et al. 2018

J Exp Clin Cancer Res

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BackgroundKindlin-1, − 2, and − 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described.MethodsTo better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n = 58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n = 438) and protein (n = 129) levels and we evaluated their correlation with the clinical outcome.ResultsWe determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients’ outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients.ConclusionThis study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors.These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0955-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Distinct expression profiles and functions of Kindlins in breast cancer

Azorin

Bonin

Moukachar

et al. 2018

J Exp Clin Cancer Res

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“…However, independent evidence for the role of kindlin-3 in BC can be taken from interrogation of the Oncomine database (http://www.oncomine.com) in which kindlin-3 ranked in the top 3% of up-regulated genes. Furthermore, in glioblastoma, kindlin-3 contributed to resistance to telozolomide and cell proliferation through Wnt signaling (Lu et al, 2017), whereas overexpression of kindlin-3 in melanoma cells led to imbalanced Rho GTP-ase activation and inhibition of cell migration (Feng et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

et al. 2019

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Studies of isolated cells, mice, and humans have demonstrated the vital role of the FERM domain protein kindlin-3 in integrin activation in certain hematopoietic and non-hematopoietic cells, consequent to binding to integrin β-subunits. To explore regulatory mechanisms, we developed a monoclonal antibody that selectively recognizes the phosphorylated form of Ser484 (pS484) in kindlin-3. Activation of platelets, HEL megakaryocytic-like cells and BT549 breast cancer cells led to enhanced expression of pS484 as assessed by immunofluorescence or Western blotting. In platelets, pS484 rose rapidly and transiently upon stimulation. When a mutant form of kindlin-3, T482S484/AA kindlin-3, was transduced into mouse megakaryocytes, it failed to support activation of integrin αIIbβ3, whereas wild-type kindlin-3 did. In MDA-MB231 breast cancer cells, expression of T482S484/AA kindlin-3 suppressed cell spreading, migration, invasion, and VEGF production. Wild-type kindlin-3 expressing cells markedly increased tumor growth in vivo, whereas T482S484/AA kindlin-3 significantly blunted tumor progression. Thus, our data establish that a unique phosphorylation event in kindlin-3 regulates its cellular functions.

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“…The wound area was measured using ImageJ software following the protocol described by [35]. The rate of cell migration was calculated based on the change in % area covered with cells between time 0 and 24 h.…”

Section: Scratch Assaymentioning

confidence: 99%

Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer

Pecinová

Alán

Brázdová

et al. 2020

Cells

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Prostate cancer is one of the most prominent cancers diagnosed in males. Contrasting with other cancer types, glucose utilization is not increased in prostate carcinoma cells as they employ different metabolic adaptations involving mitochondria as a source of energy and intermediates required for rapid cell growth. In this regard, prostate cancer cells were associated with higher activity of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), the key rate limiting component of the glycerophosphate shuttle, which connects mitochondrial and cytosolic processes and plays significant role in cellular bioenergetics. Our research focused on the role of mGPDH biogenesis and regulation in prostate cancer compared to healthy cells. We show that the 42 amino acid presequence is cleaved from N-terminus during mGPDH biogenesis. Only the processed form is part of the mGPDH dimer that is the prominent functional enzyme entity. We demonstrate that mGPDH overexpression enhances the wound healing ability in prostate cancer cells. As mGPDH is at the crossroad of glycolysis, lipogenesis and oxidative metabolism, regulation of its activity by intramitochondrial processing might represent rapid means of cellular metabolic adaptations.

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Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis

Cited by 13 publications

References 57 publications

Distinct expression profiles and functions of Kindlins in breast cancer

Distinct expression profiles and functions of Kindlins in breast cancer

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer

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