The oncogenic Golgi phosphoprotein 3 like overexpression is associated with cisplatin resistance in ovarian carcinoma and activating the NF-κB signaling pathway

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Abstract

Background

Chemo-resistance is a leading cause of tumor relapse and treatment failure in patients with ovarian cancer. The identification of effective strategies to overcome drug resistance will have a significant clinical impact on the disease.

Methods

The protein and mRNA expression of GOLPH3L in ovarian cancer cell lines and patient tissues were determined using Real-time PCR and Western blot, respectively. 177 human ovarian cancer tissue samples were analyzed by IHC to investigate the association between GOLPH3L expression and the clinicopathological characteristics of ovarian cancer patients. Functional assays, such as MTT, FACS, and Tunel assay used to determine the oncogenic role of GOLPH3L in human ovarian cancer progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of GOLPH3L promotes chemoresistance in ovarian cancer cells.

Results

The expression of GOLPH3L was markedly upregulated in ovarian cancer cell lines and tissues, and high GOLPH3L expression was associated with an aggressive phenotype and poor prognosis with ovarian cancer patients. GOLPH3L overexpression confers CDDP resistance on ovarian cancer cells; however, inhibition of GOLPH3L sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. Additionally, GOLPH3L upregulated the levels of nuclear p65 and phosphorylated inhibitor of nuclear factor Kappa-B kinase-β and IκBα, thereby activating canonical nuclear factor-κB (NF-κB) signaling.

Conclusions

Our findings suggest that GOLPH3L is a potential therapeutic target for the treatment of ovarian cancer: targeting GOLPH3L signaling may represent a promising strategy to enhance platinum response in patients with chemoresistant ovarian cancer.

Electronic supplementary material

The online version of this article (10.1186/s13046-017-0607-0) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death.

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Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic carcinoma patients. The current study examined the relevance of nuclear factor kappaB (NF-kappaB) and PI3K/Akt in the resistance of five pancreatic carcinoma cell lines towards gemcitabine. Treatment for 24 h with gemcitabine (0.04-20 micro M) led to a strong induction of apoptosis in PT45-P1 and T3M4 cells but not in BxPc-3, Capan-1 and PancTu-1 cells. These resistant cell lines exhibited a high basal NF-kappaB activity in contrast to the sensitive cell lines. Furthermore, gemcitabine showed a dose-dependent induction of NF-kappaB. At a dose of 0.04 micro M, gemcitabine still induced apoptosis in the sensitive cell lines, but did not induce NF-kappaB. In addition, NF-kappaB inhibition by MG132, sulfasalazine or the IkappaBalpha super-repressor strongly diminished the resistance against gemcitabine (0.04-20 micro M). In contrast to this obvious correlation between basal NF-kappaB activity and gemcitabine resistance, PI3K/Akt seems not to be involved in gemcitabine resistance of these cell lines. Neither did the basal Akt activity correlate with the sensitivity towards gemcitabine treatment, nor did the inhibition of PI3K/Akt by LY294002 alter gemcitabine-induced apoptosis. These results indicate that constitutive NF-kappaB activity confers resistance against gemcitabine and that modulation of this activity by pharmacological or genetic approaches may have therapeutical potential when combined with gemcitabine in the treatment of pancreatic carcinoma.

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Author and article information

Contributors

Shanyang He: hsy5g777@sina.com

Hongwei Shen: doctorshen@163.com

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 4 October 2017

Publication date PMC-release: 4 October 2017

Publication date Collection: 2017

Volume: 36

Electronic Location Identifier: 137

Affiliations

[1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Obstetrics and Gynecology, The First Affiliated Hospital, , Sun Yat-sen University, ; Zhongshan Second Road 58, Guangzhou, 510700 People’s Republic of China

[2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Ultrasonic Medicine, Fetal Medical Center, the First Affiliated Hospital, , Sun Yat-sen University, ; Guangzhou, People’s Republic of China

Article

Publisher ID: 607

DOI: 10.1186/s13046-017-0607-0

PMC ID: 5628490

PubMed ID: 28978336

SO-VID: e9d9b076-317c-421d-804c-09b07a282d20

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 June 2017

Date accepted : 25 September 2017

Funding

Funded by: the Guangdong Natural Science Foundation, China

Award ID: No.S2016A030313820

Funded by: National Natural Scientific Foundation of China

Award ID: No.81772764

Funded by: the Science and Technology Planning Project of Guangzhou City, China

Award ID: No.201704020163

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: golph3l,chemo-resistance,ovarian cancer,nuclear factor-κb (nf-κb) signaling

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: golph3l, chemo-resistance, ovarian cancer, nuclear factor-κb (nf-κb) signaling

The oncogenic Golgi phosphoprotein 3 like overexpression is associated with cisplatin resistance in ovarian carcinoma and activating the NF-κB signaling pathway

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 29

The inhibitors of apoptosis (IAPs) as cancer targets.

Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death.

Cancer genetics.

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