Abstract
Background: Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. Methods: The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. Results: We found that GLIPR1-ΔTM synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔTM to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Conclusions: Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.
| Original language | English |
|---|---|
| Article number | 122 |
| Journal | Molecular Cancer |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jun 19 2015 |
| Externally published | Yes |
Fingerprint
Keywords
- c-Myc
- Combination treatment
- CXCR4
- Docetaxel
- ERK1/2
- GLIPR1-ΔTM
- JNK
- Prostate cancer
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
Cite this
GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells. / Karanika, Styliani; Karantanos, Theodoros; Kurosaka, Shinji; Wang, Jianxiang; Hirayama, Takahiro; Yang, Guang; Park, Sanghee; Golstov, Alexei A.; Tanimoto, Ryuta; Li, Likun; Thompson, Timothy C.
In: Molecular Cancer, Vol. 14, No. 1, 122, 19.06.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells
AU - Karanika, Styliani
AU - Karantanos, Theodoros
AU - Kurosaka, Shinji
AU - Wang, Jianxiang
AU - Hirayama, Takahiro
AU - Yang, Guang
AU - Park, Sanghee
AU - Golstov, Alexei A.
AU - Tanimoto, Ryuta
AU - Li, Likun
AU - Thompson, Timothy C.
PY - 2015/6/19
Y1 - 2015/6/19
N2 - Background: Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. Methods: The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. Results: We found that GLIPR1-ΔTM synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔTM to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Conclusions: Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.
AB - Background: Docetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells. Methods: The synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model. Results: We found that GLIPR1-ΔTM synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔTM to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did. Conclusions: Our data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.
KW - c-Myc
KW - Combination treatment
KW - CXCR4
KW - Docetaxel
KW - ERK1/2
KW - GLIPR1-ΔTM
KW - JNK
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=84934279636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84934279636&partnerID=8YFLogxK
U2 - 10.1186/s12943-015-0395-0
DO - 10.1186/s12943-015-0395-0
M3 - Article
VL - 14
JO - Molecular Cancer
JF - Molecular Cancer
SN - 1476-4598
IS - 1
M1 - 122
ER -