CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Miyazawa, Yuri; Uekita, Takamasa; Ito, Yuumi; Seiki, Motoharu; Yamaguchi, Hideki; Sakai, Ryuichi

doi:10.1158/1541-7786.mcr-12-0544

Cited by 35 publications

(40 citation statements)

References 43 publications

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“…5C and D). Recently, we reported that CDCP1 may be involved in a lipid raftdependent secretary pathway (43). It is reasonable to speculate that CDCP1 also plays a role in Ras-induced cell motility and invasion by regulating focal adhesion and MMP2 activation and MMP9 secretion.…”

Section: Discussionmentioning

confidence: 96%

“…It is reasonable to speculate that CDCP1 also plays a role in Ras-induced cell motility and invasion by regulating focal adhesion and MMP2 activation and MMP9 secretion. Moreover, CDCP1 is associated with MT1-MMP, which is an activator of both MMP2 and MMP9 (43). It is speculated that CDCP1 can regulate activation of MMP2 and MMP9 through membrane trafficking of MT1-MMP to the same intracellular compartment.…”

Section: Discussionmentioning

confidence: 99%

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Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis

Uekita

Fujii²,

Miyazawa³

et al. 2014

Molecular Cancer Research

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Involvement of Ras in cancer initiation is known, but recent evidence indicates a role in cancer progression, including metastasis and invasion; however, the mechanism is still unknown. In this study, it was determined that human lung cancer cells with Ras mutations, among other popular mutations, showed significantly higher expression of CUB domain-containing protein 1 (CDCP1) than those without. Furthermore, activated Ras clearly induced CDCP1, whereas CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogated anoikis resistance, migration, and invasion induced by activated-Ras. Activation of MMP2 and secretion of MMP9, in a model of Ras-induced invasion, was found to be regulated through induction of phosphorylated CDCP1. Thus, CDCP1 is required for the functional link between Ras and Src signaling during the multistage development of human malignant tumors, highlighting CDCP1 as a potent target for treatment in the broad spectrum of human cancers associated with these oncogenes.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis

Uekita

Fujii²,

Miyazawa³

et al. 2014

Molecular Cancer Research

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“…For example, LDs appear to be not merely inert structures for lipid storage, but dynamic signaling organelles (58,59). The literature supports the cross-talk between cellular LDs and membrane lipid rafts (60)(61)(62), where multiple proteins involved in migration, including integrins (63,64) and CDCP1 (54,65), reside. On the other hand, the biophysical properties of high-lipid vs. lowlipid cells remain unknown and await investigation.…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 89%

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

102

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Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3, 4), prostate (5), pancreatic (6, 7), colon (8-12), and triple-negative breast (TNBC) (13, 14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15, 16), ovarian (17), prostate (5), and colon (9) cancers. Although CDCP1's role in TNBC metastasis has not been established to date, high CDCP1 expression has been validated as a prognostic marker of poor survival in TNBC when combined with positive node status (18).Our understanding of CDCP1's upstream regulators, its mechanism of activation, and downstream signaling continues to expand (recently reviewed in ref. 19). Studies by others (5) and our group (14) have demonstrated that CDCP1 cleavage is necessary for its activation, and recently, we have further shown that cleavage stimulates CDCP1 homodimerization (14). Homodimeric CDCP1 stimulates phosphorylation of protein kinase C δ (PKCδ) by Src kinase, leading to migration and invasion of TNBC cells in vitro (14). Adding to our knowledge of CDCP1's downstream signaling, we report that CDCP1 regulates lipid m...

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“…Anoikis is a form of cell death triggered by loss of interaction with the extracellular matrix [47]. In studies conducted by Miyazawa et al [48], autophagy was shown to be involved in anoikis of lung cancer cells caused by suppression of CDCP1. Cell death induced by knocking down CPCD1 in A549 (NSCLC) cells under suspension conditions was caspase 3 (a marker for apoptosis) independent.…”

Section: Autophagic Cell Death In Lung Cancer Cellsmentioning

confidence: 99%

Cytotoxic Autophagy in Cancer Therapy

Sharma

Alotaibi

et al. 2014

IJMS

115

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Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.

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CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Cited by 35 publications

References 43 publications

Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis

Oncogenic Ras/ERK Signaling Activates CDCP1 to Promote Tumor Invasion and Metastasis

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Cytotoxic Autophagy in Cancer Therapy

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