Protein Kinase D as a Potential Chemotherapeutic Target for Colorectal Cancer

Wei, Ning; Chu, Edward; Wipf, Peter; Schmitz, John C.

doi:10.1158/1535-7163.mct-13-0880

Cited by 58 publications

(77 citation statements)

References 40 publications

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“…Since PKD3 is upregulated and as such can be targeted in ER- BC independently of the HER2 status, we decided to test two different cell lines, MDA-MB-231 as a model for TNBC and HCC1954 as a model for ER-, HER2+ BC. We used the pan-PKD inhibitor CRT0066101, which has been shown to have anti-cancer activity in pancreatic, prostate and colorectal cancer cells (33,34). CRT0066101 induced a significant decrease in cell proliferation in both cell lines (Figs 4A, 4D and Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…IC 50 for PKD3 is 2 nM). In previous work it has been shown to be active in vivo in orthotopic animal models for pancreatic cancer and colorectal cancer (33,34). Since it can be orally administered and has no side effects in mice, when used at doses that inhibit PKD (33,34), it is an inhibitor that could be developed for clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Silencing of PKD1 and increased expression of the oncogenic versions of this kinase family, PKD2 and PKD3, has been described to contribute to progression of several epithelial cancers including breast cancer (11,13,16,17,20–22), gastric cancer (36), pancreatic cancer (37,38), colorectal cancer (34), and prostate cancer (14,39–42). We here show that the switch from PKD1 to PKD3 expression defines the transition to an aggressive breast tumor phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

Borgés

Perez

Thompson

et al. 2015

Molecular Cancer Therapeutics

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Invasive ductal carcinomas (IDCs) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize and their ability to resist to standard chemotherapy, hormone therapy or HER2 targeted therapy. Using progression tissue microarrays we here demonstrate that the serine/threonine kinase Protein Kinase D3 (PKD3) is highly up-regulated in estrogen receptor (ER)-negative tumors. We identify direct binding of the estrogen receptor to the PRKD3 gene promoter as a mechanism of inhibition of PKD3 expression. Loss of ER results in upregulation of PKD3 leading to all hallmarks of aggressive IDC, including increased cell proliferation, migration and invasion. This identifies ER-negative breast cancers as ideal for treatment with the PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment with this inhibitor targets all tumorigenic processes in vitro and decreases growth of primary tumors and metastasis in vivo. Our data strongly support the development of PKD inhibitors for clinical use for ER-negative breast cancers, including the triple-negative phenotype.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

Borgés

Perez

Thompson

et al. 2015

Molecular Cancer Therapeutics

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“…After 6 h, transfection medium was changed, and on the following day, cells were incubated for 2 h with various concentrations of H1 followed by addition of 50 ng/mL TNF-a for an additional 5 h. Firefly luciferase values were normalized with renilla activity and the reporter assays were performed in triplicate. 34 RNA interference HCT116 or HCT116 p53 ¡/¡ cells were plated at a density of 2.0£10 5 cells/ well. On the following day, specific siRNA targeting to PUMA (UCUC AUCAUGGGACUCCUG, Dharmacon; Chicago, IL) or FoxO3a (ACUCC GGGUCCAGCUCCAC, Dharmacon; Chicago, IL) was mixed with Lipofectamine 2000 in serum-free RPMI-1640 medium and added to the plated cells.…”

Section: Caspase -3 Colorimetric Assaymentioning

confidence: 99%

Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: A derivative of tetrandrine

Zhang

Liu

Wang

et al. 2015

Cancer Biology & Therapy

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Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1:A derivative of tetrandrine PUMA (p53 unregulated modulator of apoptosis), a BH3-only Bcl-2 family member, can be induced by p53-dependent and p53-independent manners. It plays an important role as regulator of cellular apoptosis. Herein, we evaluate the effects of H1 (a derivative of tetrandrine) on induction of PUMA and underlie its potential mechanism in p53-independent cytotoxic response. Anti-proliferative activity and evidently cytotoxic activity of H1 were observed in wild-type and p53 null cells. Further studies demonstrated that H1 resulted in an increase of cleaved PARP, decease of survivin and elevation of p-H2AX. What is more, H1 significantly induced PUMA expression in a concentration-and time-dependent manner and caused an increase of Bax/Bcl-2 ratio in p53 null cells. Of note, knockdown of PUMA attenuated cytotoxic activity of H1. Further studies demonstrated that inhibition of AKT/FoxO3a signaling contributed to H1-mediated PUMA induction. Targeted suppression of AKT/FoxO3a signaling by siRNA could overcome H1-mediated PUMA induction. In addition, H1 significantly suppressed NF-kB activity and caused an increase of early apoptotic and late apoptotic cells, and elevated caspase-3 activity. Taken together, we found that inhibition of AKT/ FoxO3a signaling may contribute to H1-mediated PUMA induction, suggesting that inhibition of AKT/FoxO3a signaling result in PUMA expression in response to p53-independent cytotoxic effects of H1.

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“…PKD signaling has been implicated in a wide range of human tumors, including breast, pancreatic, prostate, and glioblastoma. Our laboratory has recently demonstrated that PKD2-mediated signaling pathways, including RAS/RAF/ERK, PI3K/AKT/mTOR, and NF-κB, are activated in human CRC [18]. We also observed that PKD1 was only expressed in normal colon cells and not in human colorectal cancer cells.…”

Section: Introductionmentioning

confidence: 86%

The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells

Wei

Chu

et al. 2014

Oncotarget

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Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis. The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies. However, the clinical efficacy of regorafenib is quite limited. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance. Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes. Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells. Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation. This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27. This combination also yielded enhanced inhibition of ERK, AKT, and NF-κB signaling. Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC.

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Protein Kinase D as a Potential Chemotherapeutic Target for Colorectal Cancer

Cited by 58 publications

References 40 publications

Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: A derivative of tetrandrine

The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells

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