Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1

Francesca Maddalena, Lorenza Sisinni, Giacomo Lettini, Valentina Condelli, Danilo Swann Matassa, Annamaria Piscazzi, Maria Rosaria Amoroso, Giuseppe La Torre, Franca Esposito, Matteo Landriscina

Research output: Contribution to journalArticle

Abstract

TRAP1 is a mitochondrial antiapoptotic protein up-regulated in several human malignancies. However, recent evidences suggest that TRAP1 is also localized in the endoplasmic reticulum (ER) where it is involved in ER stress protection and protein quality control of tumor cells. Based on the mechanistic link between ER stress, protection from apoptosis and drug resistance, we questioned whether these novel roles of TRAP1 are relevant for its antiapoptotic function. Here, we show for the first time that: i) TRAP1 expression is increased in about 50% of human breast carcinomas (BC), and ii) the ER stress protecting activity of TRAP1 is conserved in human tumors since TRAP1 is co-upregulated with the ER stress marker, BiP/Grp78. Notably, ER-associated TRAP1 modulates mitochondrial apoptosis by exerting a quality control on 18kDa Sorcin, a TRAP1 mitochondrial client protein involved in TRAP1 cytoprotective pathway. Furthermore, this TRAP1 function is relevant in favoring resistance to paclitaxel, a microtubule stabilizing/ER stress inducer agent widely used in BC therapy. Indeed, the transfection of a TRAP1 deletion mutant, whose localization is restricted to the ER, in shTRAP1 cells enhances the expression of mitochondrial Sorcin and protects from apoptosis induced by ER stress agents and paclitaxel. Furthermore, BC cells adapted to paclitaxel or ER stress inducers share common resistance mechanisms: both cell models exhibit cross-resistance to single agents and the inhibition of TRAP1 by siRNAs or gamitrinib, a mitochondria-directed HSP90 family inhibitor, in paclitaxel-resistant cells rescues the sensitivity to paclitaxel. These results support the hypothesis that ER-associated TRAP1 is responsible for an extramitochondrial control of apoptosis and, therefore, an interference of ER stress adaptation through TRAP1 inhibition outside of mitochondria may be considered a further compartment-specific molecular approach to rescue drug-resistance.

Original languageEnglish
Pages (from-to)895-906
Number of pages12
JournalMolecular Oncology
Volume7
Issue number5
DOIs
Publication statusPublished - Oct 2013

Fingerprint

Endoplasmic Reticulum Stress
Mitochondrial Proteins
Quality Control
Breast Neoplasms
Paclitaxel
Endoplasmic Reticulum
Apoptosis
Drug Resistance
Mitochondria
Neoplasms
Heat-Shock Proteins
Microtubules
Transfection

Keywords

  • Apoptosis
  • Breast carcinoma
  • Drug resistance
  • ER stress
  • Paclitaxel
  • TRAP1

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Maddalena, F., Sisinni, L., Lettini, G., Condelli, V., Matassa, D. S., Piscazzi, A., ... Landriscina, M. (2013). Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Molecular Oncology, 7(5), 895-906. https://doi.org/10.1016/j.molonc.2013.04.009

Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. / Maddalena, Francesca; Sisinni, Lorenza; Lettini, Giacomo; Condelli, Valentina; Matassa, Danilo Swann; Piscazzi, Annamaria; Amoroso, Maria Rosaria; La Torre, Giuseppe; Esposito, Franca; Landriscina, Matteo.

In: Molecular Oncology, Vol. 7, No. 5, 10.2013, p. 895-906.

Research output: Contribution to journalArticle

Maddalena, F, Sisinni, L, Lettini, G, Condelli, V, Matassa, DS, Piscazzi, A, Amoroso, MR, La Torre, G, Esposito, F & Landriscina, M 2013, 'Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1', Molecular Oncology, vol. 7, no. 5, pp. 895-906. https://doi.org/10.1016/j.molonc.2013.04.009
Maddalena, Francesca ; Sisinni, Lorenza ; Lettini, Giacomo ; Condelli, Valentina ; Matassa, Danilo Swann ; Piscazzi, Annamaria ; Amoroso, Maria Rosaria ; La Torre, Giuseppe ; Esposito, Franca ; Landriscina, Matteo. / Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. In: Molecular Oncology. 2013 ; Vol. 7, No. 5. pp. 895-906.
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