TRAP1 regulates autophagy in lung cancer cells

Inês A. Barbosa, Ignacio Vega-Naredo, Rute Loureiro, Ana F. Branco, Rita Garcia, Patricia M. Scott, Paulo J. Oliveira

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background: Expression of TRAP1, a member of the HSP90 chaperone family, has been implicated in tumour protective effects, based on its differential mitochondrial localization and function. Design: This work was designed to provide new insights into the pathways involved in TRAP1-provided cytoprotection on NSCLC. For this, TRAP1-depleted A549 human NSCLC cells and MRC-5 normal lung fibroblasts were produced using a siRNA approach and main cellular quality control mechanisms were investigated. Results: TRAP1-depleted A549 cells displayed decreased cell viability likely due to impaired mitochondrial function including decreased ATP/AMP ratio, oxygen consumption and membrane potential, as well as increased apoptotic indicators. Furthermore, the negative impact of TRAP1 depletion on mitochondrial function was not observed in normal MRC-5 lung cells, which might be due to the differential intracellular localization of the chaperone in tumour versus normal cells. Additionally, A549 TRAP1-depleted cells showed increased autophagic flux. Functionally, autophagy inhibition resulted in decreased cell viability in both TRAP1-expressing and TRAP1-depleted tumour cells with minor effects on MRC-5 cells. Conversely, autophagy stimulation decreased cell viability of both A549 and MRC-5 TRAP1-expressing cells while in A549 TRAP1-depleted cells, increased autophagy augmented viability. Conclusions: Our results show that even though TRAP1 depletion affects both normal MRC-5 and tumour A549 cell proliferation, inhibition of autophagy per se led to a decrease in tumour cell mass, while having a reduced effect on the normal cell line. The strategy of targeting TRAP1 in NSCLC shows future potential therapeutic applications.

Original languageEnglish (US)
Article numbere12900
JournalEuropean Journal of Clinical Investigation
Volume48
Issue number4
DOIs
StatePublished - Apr 2018

Keywords

  • TRAP1
  • apoptosis
  • autophagy
  • cathepsin B
  • lung cancer
  • macroautophagy

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    Barbosa, I. A., Vega-Naredo, I., Loureiro, R., Branco, A. F., Garcia, R., Scott, P. M., & Oliveira, P. J. (2018). TRAP1 regulates autophagy in lung cancer cells. European Journal of Clinical Investigation, 48(4), [e12900]. https://doi.org/10.1111/eci.12900