Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells.

Abstract:

:Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies. The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells (P<0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells. Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP.

journal_name

Mol Cancer Ther

authors

Safaei R,Larson BJ,Cheng TC,Gibson MA,Otani S,Naerdemann W,Howell SB

doi

10.1158/1535-7163.MCT-05-0102

keywords:

subject

Has Abstract

pub_date

2005-10-01 00:00:00

pages

1595-604

issue

10

eissn

1535-7163

issn

1538-8514

pii

4/10/1595

journal_volume

4

pub_type

杂志文章
  • ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain.

    abstract::Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0953

    authors: Yiin JJ,Hu B,Schornack PA,Sengar RS,Liu KW,Feng H,Lieberman FS,Chiou SH,Sarkaria JN,Wiener EC,Ma HI,Cheng SY

    更新日期:2010-04-01 00:00:00

  • Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells.

    abstract::Hyperactivation of c-Jun NH2-terminal protein kinase (JNK) has been found in various malignant lymphocytes and inhibition of JNK activity leads to cell cycle arrest and apoptosis. However, the role of JNK activity in the oncogenic growth of T-cell acute lymphoblastic leukemia (T-ALL) cells remains largely unknown. Her...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0408

    authors: Cui J,Wang Q,Wang J,Lv M,Zhu N,Li Y,Feng J,Shen B,Zhang J

    更新日期:2009-12-01 00:00:00

  • Mechanistic studies of a novel human fusion toxin composed of vascular endothelial growth factor (VEGF)121 and the serine protease granzyme B: directed apoptotic events in vascular endothelial cells.

    abstract::The serine protease granzyme B (GrB; 25 kDa) is capable of inducing apoptosis through both caspase-dependent and caspase-independent mechanisms. We designed a novel vascular-targeting fusion construct designated as GrB/vascular endothelial growth factor (VEGF)121, which is composed of a non-heparin-binding isoform of ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Liu Y,Cheung LH,Thorpe P,Rosenblum MG

    更新日期:2003-10-01 00:00:00

  • Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells.

    abstract::Endothelins (ETs) are a group of vasoactive peptides (ET-1, ET-2 and ET-3) produced by many cell types that bind to G-protein-linked transmembrane receptors, ET-A receptors (ET-RAs) and ET-B receptors (ET-RBs). These peptides are expressed in several human tumors, including carcinomas of the breast, and have a mitogen...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Grimshaw MJ,Naylor S,Balkwill FR

    更新日期:2002-12-01 00:00:00

  • Inhibition of growth of human prostate cancer xenograft by transfection of p53 gene: gene transfer by electroporation.

    abstract::To date, there is no effective therapy for hormone-independent prostate cancer. Therefore, as a new strategy for refractory cancer, gene therapy is showing increasing promise. In this study, we attempted to use a nonviral gene transfer system, in vivo electroporation, in prostate cancer cell PC-3 xenografts with the w...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Mikata K,Uemura H,Ohuchi H,Ohta S,Nagashima Y,Kubota Y

    更新日期:2002-02-01 00:00:00

  • Generation of a canine anti-EGFR (ErbB-1) antibody for passive immunotherapy in dog cancer patients.

    abstract::Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuxi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0288

    authors: Singer J,Fazekas J,Wang W,Weichselbaumer M,Matz M,Mader A,Steinfellner W,Meitz S,Mechtcheriakova D,Sobanov Y,Willmann M,Stockner T,Spillner E,Kunert R,Jensen-Jarolim E

    更新日期:2014-07-01 00:00:00

  • TTK Inhibitors as a Targeted Therapy for CTNNB1 (β-catenin) Mutant Cancers.

    abstract::The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratifi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0342

    authors: Zaman GJR,de Roos JADM,Libouban MAA,Prinsen MBW,de Man J,Buijsman RC,Uitdehaag JCM

    更新日期:2017-11-01 00:00:00

  • Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistanc...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0253

    authors: Logsdon DP,Grimard M,Luo M,Shahda S,Jiang Y,Tong Y,Yu Z,Zyromski N,Schipani E,Carta F,Supuran CT,Korc M,Ivan M,Kelley MR,Fishel ML

    更新日期:2016-11-01 00:00:00

  • PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo.

    abstract::We have synthesized several new phenyl maleimide compounds, which are potent growth inhibitors of several human tumor cell lines. Among these, PM-20 was the most potent with an IC50 of 700 nmol/L for Hep3B human hepatoma cell growth. Two other derivatives, PM-26 and PM-38, did not inhibit Hep3B cell growth even at 100...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0485

    authors: Kar S,Wang M,Yao W,Michejda CJ,Carr BI

    更新日期:2006-06-01 00:00:00

  • Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105.

    abstract::TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasm...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0916

    authors: Liu Y,Starr MD,Brady JC,Rushing C,Pang H,Adams B,Alvarez D,Theuer CP,Hurwitz HI,Nixon AB

    更新日期:2018-10-01 00:00:00

  • Monoclonal Antibody Targeting Sialyl-di-Lewisa-Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential.

    abstract::Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal can...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0221

    authors: Tivadar ST,McIntosh RS,Chua JX,Moss R,Parsons T,Zaitoun AM,Madhusudan S,Durrant LG,Vankemmelbeke M

    更新日期:2020-03-01 00:00:00

  • TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719X.

    abstract::TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T7...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0645

    authors: Ito K,Nishio M,Kato M,Murakami H,Aoyagi Y,Ohe Y,Okayama T,Hashimoto A,Ohsawa H,Tanaka G,Nonoshita K,Ito S,Matsuo K,Miyadera K

    更新日期:2019-05-01 00:00:00

  • Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo.

    abstract::The advent of multikinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor has revolutionized the treatment of highly angiogenic malignancies such as renal cell carcinoma. Interestingly, several such inhibitors are commercially available, and they each possess diverse specific beneficial and...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0119

    authors: Liu JY,Park SH,Morisseau C,Hwang SH,Hammock BD,Weiss RH

    更新日期:2009-08-01 00:00:00

  • Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer.

    abstract::Current treatments for castration resistant prostate cancer (CRPC) largely fall into two classes: androgen receptor (AR)-targeted therapies such as the next-generation antiandrogen therapies (NGAT), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-1269

    authors: Lombard AP,Liu L,Cucchiara V,Liu C,Armstrong CM,Zhao R,Yang JC,Lou W,Evans CP,Gao AC

    更新日期:2018-10-01 00:00:00

  • Zoledronic acid inhibits osteosarcoma growth in an orthotopic model.

    abstract::Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0546

    authors: Dass CR,Choong PF

    更新日期:2007-12-01 00:00:00

  • A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy.

    abstract::The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0634

    authors: Zheng Y,Bao J,Zhao Q,Zhou T,Sun X

    更新日期:2018-04-01 00:00:00

  • Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer.

    abstract::This study aimed to investigate the antitumor and antiangiogenic effects utilizing a novel therapy regimen of metronomic topotecan and pazopanib, a multireceptor tyrosine kinase inhibitor. In vitro (Western blot) and in vivo dose-finding experiments were done following pazopanib therapy in ovarian cancer models. Pazop...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0967

    authors: Merritt WM,Nick AM,Carroll AR,Lu C,Matsuo K,Dumble M,Jennings N,Zhang S,Lin YG,Spannuth WA,Kamat AA,Stone RL,Shahzad MM,Coleman RL,Kumar R,Sood AK

    更新日期:2010-04-01 00:00:00

  • High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis.

    abstract::The present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0149

    authors: Yang ZF,Poon RT,Liu Y,Lau CK,Ho DW,Tam KH,Lam CT,Fan ST

    更新日期:2006-09-01 00:00:00

  • Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas.

    abstract::Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also inte...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-04-0328

    authors: Yuan L,Choi K,Khosla C,Zheng X,Higashikubo R,Chicoine MR,Rich KM

    更新日期:2005-09-01 00:00:00

  • Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities.

    abstract::Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-16-0337

    authors: Talbert EE,Yang J,Mace TA,Farren MR,Farris AB,Young GS,Elnaggar O,Che Z,Timmers CD,Rajasekera P,Maskarinec JM,Bloomston M,Bekaii-Saab T,Guttridge DC,Lesinski GB

    更新日期:2017-02-01 00:00:00

  • A bispecific HER2-targeting FynomAb with superior antitumor activity and novel mode of action.

    abstract::Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0046-T

    authors: Brack S,Attinger-Toller I,Schade B,Mourlane F,Klupsch K,Woods R,Hachemi H,von der Bey U,Koenig-Friedrich S,Bertschinger J,Grabulovski D

    更新日期:2014-08-01 00:00:00

  • ANG4043, a novel brain-penetrant peptide-mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice.

    abstract::Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrie...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0399

    authors: Regina A,Demeule M,Tripathy S,Lord-Dufour S,Currie JC,Iddir M,Annabi B,Castaigne JP,Lachowicz JE

    更新日期:2015-01-01 00:00:00

  • A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities.

    abstract::We discovered a thalidomide analogue [5-hydroxy-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33)] with antiproliferative activity against nine cancer cell lines in vitro. Flow cytometric analyses showed that the compound caused G2-M arrest, which occurred mainly at the mitotic phase. In addition, immunofluores...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0254

    authors: Li PK,Pandit B,Sackett DL,Hu Z,Zink J,Zhi J,Freeman D,Robey RW,Werbovetz K,Lewis A,Li C

    更新日期:2006-02-01 00:00:00

  • Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse.

    abstract::R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well as the identification of the principal metabolites in hepatic microsomes, plasma, and urine. Following microsomal ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Nutley BP,Raynaud FI,Wilson SC,Fischer PM,Hayes A,Goddard PM,McClue SJ,Jarman M,Lane DP,Workman P

    更新日期:2005-01-01 00:00:00

  • eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling.

    abstract::Activation of translation initiation is essential for the malignant phenotype and is emerging as a potential therapeutic target. Translation is regulated by the expression of translation initiation factor 4E (eIF4E) as well as the interaction of eIF4E with eIF4E-binding proteins (e.g., 4E-BP1). Rapamycin inhibits tran...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-2357

    authors: Soni A,Akcakanat A,Singh G,Luyimbazi D,Zheng Y,Kim D,Gonzalez-Angulo A,Meric-Bernstam F

    更新日期:2008-07-01 00:00:00

  • Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells.

    abstract::Chemoresistance of ovarian carcinoma has been associated previously to the absence of Bcl-x(L) expression downregulation in response to cisplatin. Among BH3-mimetic molecules constituting promising anticancer agents able to inhibit the activity of antiapoptotic Bcl-2 family proteins, we evaluated the effect of one of ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0493

    authors: Simonin K,Brotin E,Dufort S,Dutoit S,Goux D,N'diaye M,Denoyelle C,Gauduchon P,Poulain L

    更新日期:2009-11-01 00:00:00

  • Tunicamycin potentiates cisplatin anticancer efficacy through the DPAGT1/Akt/ABCG2 pathway in mouse Xenograft models of human hepatocellular carcinoma.

    abstract::Hepatocellular carcinoma is highly chemoresistant, and ATP-binding cassette subfamily G member 2 (ABCG2) is thought to play a critical role in this drug resistance. The present study aims to develop effective therapeutic strategies to decrease ABCG2 expression level and to surmount drug resistance in hepatocellular ca...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0201

    authors: Hou H,Sun H,Lu P,Ge C,Zhang L,Li H,Zhao F,Tian H,Zhang L,Chen T,Yao M,Li J

    更新日期:2013-12-01 00:00:00

  • Survivin, a cancer target with an emerging role in normal adult tissues.

    abstract::Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-05-0375

    authors: Fukuda S,Pelus LM

    更新日期:2006-05-01 00:00:00

  • Prognostic role of KiSS-1 and possibility of therapeutic modality of metastin, the final peptide of the KiSS-1 gene, in urothelial carcinoma.

    abstract::The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene product was isolated from human placenta as the ligand of GPR54, a G protein-coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0521

    authors: Takeda T,Kikuchi E,Mikami S,Suzuki E,Matsumoto K,Miyajima A,Okada Y,Oya M

    更新日期:2012-04-01 00:00:00

  • D,L-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells.

    abstract::D,L-Sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L-isomer, inhibits the growth of human prostate cancer cells in culture and in vivo and retards cancer development in a transgenic mouse model of prostate cancer. We now show that SFN treatment causes transcriptional repression of androgen r...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0104

    authors: Kim SH,Singh SV

    更新日期:2009-07-01 00:00:00