Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells

Maria Chiara Anania, Elena Cetti, Daniele Lecis, Katia Todoerti, Alessandro Gulino, Giuseppe Mauro, Tiziana Di Marco, Loredana Cleris, Sonia Pagliardini, Giacomo Manenti, Beatrice Belmonte, Claudio Tripodo, Antonino Neri, Angela Greco

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Abstract

Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer.

Original languageEnglish
Pages (from-to)201-211
Number of pages11
JournalCancer Letters
Volume410
DOIs
Publication statusPublished - Dec 1 2017

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Thyroid Gland
Small Interfering RNA
Neoplasms
Autophagy
Thyroid Neoplasms
Coatomer Protein
Unfolded Protein Response
Endoplasmic Reticulum Stress
Essential Genes
Heat-Shock Proteins
Heterografts
Cell Survival
Homeostasis
Cell Death
Therapeutics
Apoptosis
Phenotype
Lipids
Growth
Genes

Keywords

  • Journal Article

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Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells. / Anania, Maria Chiara; Cetti, Elena; Lecis, Daniele; Todoerti, Katia; Gulino, Alessandro; Mauro, Giuseppe; Di Marco, Tiziana; Cleris, Loredana; Pagliardini, Sonia; Manenti, Giacomo; Belmonte, Beatrice; Tripodo, Claudio; Neri, Antonino; Greco, Angela.

In: Cancer Letters, Vol. 410, 01.12.2017, p. 201-211.

Research output: Contribution to journalArticle

Anania, MC, Cetti, E, Lecis, D, Todoerti, K, Gulino, A, Mauro, G, Di Marco, T, Cleris, L, Pagliardini, S, Manenti, G, Belmonte, B, Tripodo, C, Neri, A & Greco, A 2017, 'Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells', Cancer Letters, vol. 410, pp. 201-211. https://doi.org/10.1016/j.canlet.2017.09.024
Anania, Maria Chiara ; Cetti, Elena ; Lecis, Daniele ; Todoerti, Katia ; Gulino, Alessandro ; Mauro, Giuseppe ; Di Marco, Tiziana ; Cleris, Loredana ; Pagliardini, Sonia ; Manenti, Giacomo ; Belmonte, Beatrice ; Tripodo, Claudio ; Neri, Antonino ; Greco, Angela. / Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells. In: Cancer Letters. 2017 ; Vol. 410. pp. 201-211.
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AU - Todoerti, Katia

AU - Gulino, Alessandro

AU - Mauro, Giuseppe

AU - Di Marco, Tiziana

AU - Cleris, Loredana

AU - Pagliardini, Sonia

AU - Manenti, Giacomo

AU - Belmonte, Beatrice

AU - Tripodo, Claudio

AU - Neri, Antonino

AU - Greco, Angela

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N2 - Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer.

AB - Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer.

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