SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial–mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway

Li, Xuqi; Ma, Qingyong; Xu, Qinhong; Liu, Han; Liu, Jing; Duan, Wanxing; Bhat, Kruttika; Wang, Fengfei; Wu, Erxi; Wang, Zheng

doi:10.1016/j.canlet.2012.02.035

Cited by 164 publications

(133 citation statements)

References 28 publications

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“…Hedgehog pathway is necessary not only for maintenance of the stem cell compartment, but also for the induction of metastasis and regulation of EMT (22,27). Recently published data suggest that inhibition of the CXCR4/CXCL12 signaling pathway may also downregulate the hedgehog pathway (28). However, consistent with previous studies (29), we found that AMD3100 treatment did not result in inhibition of the hedgehog pathway in CSCs (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 89%

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

Balic

Sørensen

Trabulo

et al. 2014

Molecular Cancer Therapeutics

135

116

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Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehoginduced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. Mol Cancer Ther; 13(7); 1758-71. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 89%

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

Balic

Sørensen

Trabulo

et al. 2014

Molecular Cancer Therapeutics

135

116

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“…pancreatic cancer EMT through the activation of the Hedgehog pathway (31). The present study demonstrated that in the CXCR4 siRNA group of cells, the expression of N-cadherin and MMP2/9 were attenuated, while E-cadherin was upregulated, and the same results were observed in xenograft models.…”

supporting

confidence: 79%

Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma

Duan

Zhang

Wang³

et al. 2016

Oncology Letters

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Abstract. Aberrant overexpression of C-X-C chemokine receptor type 4 (CXCR4) is a critical event during tumor metastasis. It has been previously reported that the expression of CXCR4 is linked with epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC) tissues derived from patients. The present study addresses the role of CXCR4 in EMT in tongue squamous cell carcinoma (TSCCA) cells in vitro and in xenograft models. Small interfering (si) RNA sequences targeting the CXCR4 gene were transfected into TSCCA cells. Cell migration, invasion, apoptosis and EMT markers were determined in TSCCA cells using wound healing and Transwell assays, Annexin V/propdidum iodide double staining and western blot analysis, respectively. In vivo, tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Phenotypic EMT markers and regulatory factors were detected in the tumor tissues derived from the mice. In vitro, silencing of CXCR4 expression suppressed cell migration and invasion, and induced apoptosis. The protein expression of the EMT-associated markers N-cadherin and matrix metalloproteinases 2/9 were attenuated, while E-cadherin was increased. In vivo, CXCR4 siRNA inhibited tumor growth, and EMT-associated proteins had similar expression patterns to the experimental results observed in vitro. In conclusion, the present study demonstrated that CXCR4 silencing suppressed EMT in OSCC, thus affecting tumor metastasis.

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“…Proteins of the Hedgehog (Hh) signaling pathway, an important regulator of human embryonic development, are highly expressed in pancreatic cancer tissues or cells, and their expression appears to correlate to the occurrence, development and biological behavior of tumor cells (4). Hh signaling activation is a common event in pancreatic cancer (5).…”

Section: Introductionmentioning

confidence: 99%

Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the Hedgehog signaling pathway

Qin

Dang

et al. 2014

Molecular Medicine Reports

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Abstract. We previously demonstrated that resveratrol (Res) regulates the expression of PKC α and δ, to eventually inhibit growth and induce apoptosis in human gastric cancer cells. In the present study, the effect of Res on the growth of human pancreatic cancer cells was investigated, to further unveil the underlying mechanism. The human pancreatic cancer cell line MIA PaCa-2 was treated with three different concentrations of Res. Cell proliferation was assessed by the MTT assay, and apoptosis was detected by flow cytometry. Reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis were used to measure the mRNA and protein levels of the Hedgehog (Hh) signaling proteins Ihh, Ptch and Smo. Our results revealed that Res can inhibit the cell proliferative ability in a time-and dose-dependent manner. The number of formed colonies in the Res-and 5-Fu (positive control)-treated groups was decreased as compared to the negative control group. Res further induced apoptosis of MIA PaCa-2 cells in a dose-dependent manner. In addition, the levels of Ihh, Ptch and Smo were decreased by Res treatment. Our findings suggest that Res inhibits proliferation and induces apoptosis of MIA PaCa-2 pancreatic cancer cells in vitro, which may be related to its inhibitory effect on the Hh signaling pathway.

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SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial–mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway

Cited by 164 publications

References 28 publications

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling

Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma

Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the Hedgehog signaling pathway

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