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Open AccessArticle

The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

1
INSERM U1218, F-33076 Bordeaux, France
2
Department of Life and Health Sciences, University of Bordeaux, F-33000 Bordeaux, France
3
Department of Pathology, Bergonié Cancer Institute, F-33076 Bordeaux, France
4
University of Lyon, F-69361 Lyon CEDEX 07, France
5
Univ-Lyon, CarMeN laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, Hospital Cardiology, B13 Building, Lyon East, F-69500 Bron, France
6
INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux (CRCTB), F-33000 Bordeaux, France
*
Authors to whom correspondence should be addressed.
Current affiliations: INSERM U1037, Cancer Research Center of Toulouse (CRCT) and Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, F-31037 Toulouse, France.
Cancers 2018, 10(11), 439; https://doi.org/10.3390/cancers10110439
Received: 22 October 2018 / Accepted: 9 November 2018 / Published: 14 November 2018
(This article belongs to the Special Issue Ion Channels in Cancer)
By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS. View Full-Text
Keywords: klotho; cancer; liposarcoma; calcium; ER stress; translocon; IGF-1; ERK; gemcitabine; TRPC6; channels klotho; cancer; liposarcoma; calcium; ER stress; translocon; IGF-1; ERK; gemcitabine; TRPC6; channels
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MDPI and ACS Style

Delcroix, V.; Mauduit, O.; Tessier, N.; Montillaud, A.; Lesluyes, T.; Ducret, T.; Chibon, F.; Van Coppenolle, F.; Ducreux, S.; Vacher, P. The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas. Cancers 2018, 10, 439.

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