Interaction of CCN1 with αvβ3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells

Long, Qi; Zhou, Ming; Liu, Xiaogang; Du, Yifan; Fan, Jinhai; Li, Xiang; He, Da-lin

doi:10.1097/cad.0b013e328363046d

Cited by 30 publications

(27 citation statements)

References 21 publications

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“…The drug efflux pumps ABCB1 (MDR1/P-glycoprotein) and ABCC1 (MRP1) have been linked to the resistance of PDAC cells to gemcitabine (37,38). CYR61 has been previously reported to regulate expression of the drug efflux pump MDR1/P-glycoprotein in renal cell carcinoma (39), but it has not been studied in PDAC. We examined the effect of CYR61 on the expression of these factors associated with gemcitabine resistance.…”

Section: Cyr61 Does Not Regulate Expression Of Other Gemcitabine Resimentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61. We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

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Section: Cyr61 Does Not Regulate Expression Of Other Gemcitabine Resimentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

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“…The intention is to scrutinize for new insights and potential for future investigations, basic and translational. CCN1 (Cyr61) Long et al (2013) studying a number of renal carcinoma cell lines showed upregulation of multidrug resistance in vinblastine resistant cell lines correlated with increased expression of CCN1 by ELISA. This was mediated by αVβ3 integrin blocked by an antibody with CCN1 treatment specifically triggering the PI3K/Akt pathway.…”

Section: Ccn Proteins and Cancermentioning

confidence: 99%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

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“…Integrins initiate a variety of downstream signaling events including survival or death pathways in response to ECM ligation (5 FN. Upon activation of the integrin αVβ3 receptor, downstream molecules, including phosphatidylinositol 3 kinase (PI3K)/Akt, are phosphorylated, which increases cell tolerance to chemotherapy, resulting in secondary resistance in a variety of ways (6). In our previous study, we demonstrated that rVBMDMP binds αvβ3 integrins and enhances the growth inhibitory activity of cisplatin in A549 cells (7).…”

Section: Introductionmentioning

confidence: 99%

Effects of VBMDMP on the reversal of cisplatin resistance in human lung cancer A549/DDP cells

Wang¹,

Zhang²,

Zhang³

et al. 2014

Oncology Reports

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Abstract.Tumor drug resistance is a major obstacle to cancer chemotherapy. We previously constructed a fusion protein based on two tumstatin-derived sequences named recombinant VBMDM (rVBMDMP). We preliminarily confirmed its inhibition of HUVEC and colon cancer cell growth. The present study further systematically observed the inhibitory effect of rVBMDMP on lung cancer cell growth and analyzed a possible mechanism to provide a theoretical basis for the development of new antitumor protein drugs. The effect of rVBMDMP on human lung adenocarcinoma (A549) and cisplatin-resistant human lung adenocarcinoma (A549/DDP) cell proliferation was evaluated by MTS assay. Hoechst 33342 staining performed together with fluorescence microscopy and immunoblot analysis were used to examine the effects of rVBMDMP on the apoptosis of A549/DDP cells. A protein phosphorylation chip was used to identify changes in rVBMDMP-induced signaling protein phosphorylation. Changes in the phosphatidylinositol 3 kinase (PI3K)/Akt signal transduction pathway and expression of multidrug resistance protein (MRP-2)-related molecules following rVBMDMP treatment in A549/DDP cells were evaluated by western blot analysis. A lung cancer xenograft model was used to evaluate the reversal effect of rVBMDMP on drug-resistance of A549/ DDP cell tumors to cisplatin in vivo. The results demonstrated that rVBMDMP increased the phosphorylation of 79 signaling proteins, including focal adhesion kinase (FAK), caspase-6, Fas, FasL and FAF1 and downregulated 30 signaling proteins, including integrin αV, integrin β3, PI3K/Akt, NF-κB and MRP-2 compared with the controls. rVBMDMP also increased the sensitivity of A549 and A549/DDP cells to cisplatin and directly induced apoptosis, which may be related to MRP-2 and Bcl-2 downregulation. The effects of growth inhibition and apoptosis induction of rVBMDMP on A549/DDP cells may be related to the inhibition of integrin αVβ3 and PI3K/Akt protein phosphorylation. Finally, we observed an increase in cancer cell sensitivity to cisplatin by rVBMDMP using the A549/DDP cell xenograft model in nude mice. Our study suggests that rVBMDMP may be an effective potential chemotherapy sensitizer and may be a viable drug candidate in anticancer therapies.

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Interaction of CCN1 with αvβ3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells

Cited by 30 publications

References 21 publications

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

CCN family of proteins: critical modulators of the tumor cell microenvironment

Effects of VBMDMP on the reversal of cisplatin resistance in human lung cancer A549/DDP cells

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