Clusterin Regulates Drug-Resistance in Melanoma Cells

Höeller, Christoph; Pratscher, Barbara; Thallinger, Christiane; Winter, Dorian; Fink, Dieter; Kovacic, Boris; Sexl, Veronika; Wacheck, Volker; Gleave, Martin; Pehamberger, Hubert; Jansen, Burkhard

doi:10.1111/j.0022-202x.2005.23720.x

Cited by 45 publications

(41 citation statements)

References 30 publications

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“…The CLU protein is thought to be involved in processes such as carcinogenesis, tumor progression, immune system regulation and apoptosis,24 and it is expressed strongly in different tumor types 25, 26, 27. Moreover, in colon carcinoma28 and prostate cancer,29 the CLU levels reflect disease progression and the biological aggressiveness of the tumor.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Ortega-Martinez

Gardeazábal

Erramuzpe

et al. 2016

Intl Journal of Cancer

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Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I–II patients may still develop metastasis during follow‐up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow‐up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease‐free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early‐stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival.

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Section: Discussionmentioning

confidence: 99%

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Ortega-Martinez

Gardeazábal

Erramuzpe

et al. 2016

Intl Journal of Cancer

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“…Its role has been documented in prostate cancer for paclitaxel/docetaxel resistance [41] as well as in renal [42], and melanoma [43],breast tumor cells [9,44]. Most significantly, sCLU expression is documented to lead to broad-based resistance to other unrelated chemotherapeutic agents such as doxorubicin [9,45], DDP [9,45,46], and etoposide [47].…”

Section: Discussionmentioning

confidence: 99%

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Zhang¹,

Zhang²,

Liu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). Methods: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549^DDPin vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. Results: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549^DDP and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549^DDP cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204}, and vice versa. Inhibition of pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204} was sufficient to induce significant recover y in chemosensitivity to DDP in A549^DDP in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. Conclusions: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy.

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“…The lack of effect of sCLU on the growth of cancer cells is consistent with previous observations indicating a prosurvival, antiapoptotic effect of this protein form. Transfection of sCLU in cancer cells is associated with increased survival in the presence of cytotoxic drugs (40)(41)(42), whereas down-regulation of sCLU by means of antisense oligonucleotides decreases drug resistance in cancer models (27,28,32,(42)(43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

et al. 2007

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Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with ''full-length'' CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to A-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and A-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to A-actinin. [Cancer Res 2007; 67(21):10325-33]

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Clusterin Regulates Drug-Resistance in Melanoma Cells

Cited by 45 publications

References 30 publications

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

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