TUBB3 Reverses Resistance to Docetaxel and Cabazitaxel in Prostate Cancer

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.

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KIFC1 Inhibitor CW069 Induces Apoptosis and Reverses Resistance to Docetaxel in Prostate Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8020225 ◽

2019 ◽

Vol 8 (2) ◽

pp. 225 ◽

Cited By ~ 8

Author(s):

Yohei Sekino ◽

Naohide Oue ◽

Yuki Koike ◽

Yoshinori Shigematsu ◽

Naoya Sakamoto ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Viability ◽

Cell Lines ◽

Cancer Progression ◽

Parental Cell ◽

Resistant Cell ◽

Potential Strategy ◽

Kinesin Family ◽

Resistant Cells

Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance.

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ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942

Oncogene ◽

10.1038/s41388-019-1008-y ◽

2019 ◽

Vol 39 (3) ◽

pp. 651-663 ◽

Cited By ~ 3

Author(s):

Georgina P. Sava ◽

Hailing Fan ◽

Rosemary A. Fisher ◽

Sabrina Lusvarghi ◽

Sunil Pancholi ◽

...

Keyword(s):

Cell Lines ◽

Abc Transporter ◽

Abc Transporters ◽

Cancer Therapeutics ◽

Resistant Cell ◽

Cross Resistance ◽

Common Mechanism ◽

Mechanism Of Resistance ◽

Resistant Lines ◽

Resistant Cells

Abstract The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.

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Inhibition of Akt/Survivin Pathway Synergizes the Antileukemia Effect of Nutlin-3 in Acute Lymphoblastic Leukemia Cells.

Blood ◽

10.1182/blood.v110.11.2790.2790 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2790-2790

Author(s):

Ningxi Zhu ◽

Lubing Gu ◽

Muxiang Zhou

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Pi3k Inhibitor ◽

Pten Expression ◽

Pten Gene ◽

Akt Inhibitor ◽

Cancer Cell Growth ◽

Pi3k Inhibitor Ly294002 ◽

Mdm2 Antagonist

PI3k/Akt and p53 pathways are known to play anti- and pro-apoptotic roles in cell death, respectively. High level of PI3k/Akt activation by loss of PTEN expression and inactivation of p53 by overexpression of MDM2 are associated with cancer cell growth and progression. Here, we report that inhibition of PI3k/Akt either by PI3k inhibitor Ly294002 or by expression of PTEN synergizes the MDM2 antagonist nutlin-3 in inducing apoptosis in acute lymphoblastic leukemia (ALL). First, we tested the effect of nutlin-3 on induction of p53 and apoptosis in a set of ALL cell lines with wild-type (wt) p53 and MDM2 overexpression. The p53 was induced by nutlin-3 in all cell lines tested but induction of apoptosis was different in cells with distinct PTEN status. Nutlin-3 induced potent apoptosis in cell lines with PTEN expression but not in cell lines without PTEN expression. Consistent with the apoptotic effects, nutlin-3 significantly downregulated expression of survivin in PTEN-positive cells but not in PTEN-negative cells. When these nutlin-3 resistant cells were simultaneously treated with the PI3K inhibitor Ly294002 or pre-transfected with PTEN gene, their sensitivity to nutlin-3 was increased with a concomitant downregulation of survivin. Furthermore, direct silencing of survivin by siRNA increased the apoptotic effect of nutlin-3 on PTEN-negative ALL cells. Taken together, our results suggest that Akt-mediated survivin upregulation in PTEN-negative ALL cells attenuate nutlin-3 induced apoptosis, and combination of MDM2 antagonist and PI3K/Akt inhibitor may be a promising approach in the treatment of refractory ALL.

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Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

Scientific Reports ◽

10.1038/s41598-019-50220-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Florian Handle ◽

Stefan Prekovic ◽

Christine Helsen ◽

Thomas Van den Broeck ◽

Elien Smeets ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Parp Inhibitor ◽

Resistance Mechanisms ◽

Resistant Cell ◽

Cross Resistance ◽

Castration Resistant Prostate Cancer ◽

Tissue Samples ◽

Cellular Models ◽

Castration Resistant

Abstract Inhibition of the androgen receptor (AR) by second-generation anti-androgens is a standard treatment for metastatic castration resistant prostate cancer (mCRPC), but it inevitably leads to the development of resistance. Since the introduction of highly efficient AR signalling inhibitors, approximately 20% of mCRPC patients develop disease with AR independent resistance mechanisms. In this study, we generated two anti-androgen and castration resistant prostate cancer cell models that do not rely on AR activity for growth despite robust AR expression (AR indifferent). They are thus resistant against all modern AR signalling inhibitors. Both cell lines display cross-resistance against the chemotherapeutic drug docetaxel due to MCL1 upregulation but remain sensitive to the PARP inhibitor olaparib and the pan-BCL inhibitor obatoclax. RNA-seq analysis of the anti-androgen resistant cell lines identified hyper-activation of the E2F cell-cycle master regulator as driver of AR indifferent growth, which was caused by deregulation of cyclin D/E, E2F1, RB1, and increased Myc activity. Importantly, mCRPC tissue samples with low AR activity displayed the same alterations and increased E2F activity. In conclusion, we describe two cellular models that faithfully mimic the acquisition of a treatment induced AR independent phenotype that is cross-resistant against chemotherapy and driven by E2F hyper-activation.

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TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy

Cancers ◽

10.3390/cancers12020334 ◽

2020 ◽

Vol 12 (2) ◽

pp. 334 ◽

Cited By ~ 1

Author(s):

Jin Won Kim ◽

Ahrum Min ◽

Seock-Ah Im ◽

Hyemin Jang ◽

Yu Jin Kim ◽

...

Keyword(s):

Cell Lines ◽

Brca2 Mutation ◽

Acquired Resistance ◽

Xenograft Model ◽

Underlying Mechanism ◽

Resistant Cell ◽

Cross Resistance ◽

Topoisomerase 1 ◽

Underlying Mechanisms ◽

Resistant Cells

The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.

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IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9

Endocrine Related Cancer ◽

10.1530/erc-13-0222 ◽

2013 ◽

Vol 20 (5) ◽

pp. 677-689 ◽

Cited By ~ 11

Author(s):

Holger H H Erb ◽

Regina V Langlechner ◽

Patrizia L Moser ◽

Florian Handle ◽

Tineke Casneuf ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Cellular Proliferation ◽

Tissue Expression ◽

Type I ◽

Regulatory Factor ◽

Quantitative Real Time Pcr ◽

Antiproliferative Effects ◽

Protein Levels

Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNα2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2.

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Activity of different anthracycline formulations in hormone-refractory prostate cancer cell lines: Role of golgi apparatus

Journal of Cellular Physiology ◽

10.1002/jcp.22654 ◽

2011 ◽

Vol 226 (11) ◽

pp. 3035-3042 ◽

Cited By ~ 4

Author(s):

Francesco Fabbri ◽

Wainer Zoli ◽

Silvia Carloni ◽

Paola Ulivi ◽

Chiara Arienti ◽

...

Keyword(s):

Prostate Cancer ◽

Golgi Apparatus ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Hormone Refractory Prostate Cancer ◽

Prostate Cancer Cell Lines ◽

Hormone Refractory

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Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

Endocrine Related Cancer ◽

10.1530/erc-15-0343 ◽

2015 ◽

Vol 23 (1) ◽

pp. 35-45 ◽

Cited By ~ 22

Author(s):

Jan Kroon ◽

Martin Puhr ◽

Jeroen T Buijs ◽

Geertje van der Horst ◽

Daniëlle M Hemmer ◽

...

Keyword(s):

Prostate Cancer ◽

Glucocorticoid Receptor ◽

Cell Lines ◽

Chemotherapy Resistance ◽

Clinical Problem ◽

Dependent Manner ◽

Ru 486 ◽

Docetaxel Resistance ◽

Docetaxel Treatment

Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

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Avian Sarcoma Virus Transformed Hamster Cells made Resistant to Ethidium Bromide

Journal of Cell Science ◽

10.1242/jcs.16.3.603 ◽

1974 ◽

Vol 16 (3) ◽

pp. 603-621

Author(s):

C. ALTANER ◽

J. MATOSKA

Keyword(s):

Cell Lines ◽

Ethidium Bromide ◽

Virus Genome ◽

Resistant Cell ◽

Resistant Cell Line ◽

Avian Sarcoma Virus ◽

Sarcoma Virus ◽

Original Cell ◽

Avian Sarcoma ◽

Resistant Cells

Hamster cells transformed with the Schmidt-Ruppin strain of avian sarcoma virus were selected for resistance to ethidium bromide (EB). The resistant cell lines proliferated in the presence of up to 30 µg/ml EB. From avian sarcoma virus-transformed hamster cells already resistant to bromodeoxy-uridine (BrdU), ethidium bromide-resistant cells which were able to grow in 10 µg/ml EB were also prepared. These cells remain deficient in thymidine kinase activity and are suitable for selective preparation of hybrid cells. The EB resistance was genetically stable. The EB-resistant cell lines, and doubly resistant cells (BrdU, EB) showed no differences in mitochondrial ultrastructure compared with the original cell lines. Thymidine incorporation into mitochondrial DNA was not influenced by EB resistance. All resistant cell lines, including the doubly resistant cell line, contained the avian sarcoma virus genome. The number of cells needed for positive rescue experiments for avian sarcoma virus genome by cell fusion with permissive chicken embryo cells was the same as with the original cell lines. The single EB-resistant cell lines contained R-type virus-like particles, while in BrdU-resistant and doubly resistant cells the R-type particles were absent. The possible nature of EB resistance is discussed.

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