Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis

Devora Champa, Arturo Orlacchio, Bindi Patel, Michela Ranieri, Anton Shemetov, Vladislav Verkhusha, Ana Maria Cuervo, Antonio Di Cristofano

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Poorly differentiated and anaplastic thyroid carcinomas are very aggressive, almost invariably lethal neoplasms for which no effective treatment exists. These tumors are intrinsically resistant to cell death, even when their driver oncogenic signaling pathways are inhibited. We have undertaken a detailed analysis, in mouse and human thyroid cancer cells, of the mechanism through which Obatoclax, a pan-inhibitor of the anti-apoptotic proteins of the BCL2 family, effectively reduces tumor growth in vitro and in vivo. We demonstrate that Obatoclax does not induce apoptosis, but rather necrosis of thyroid cancer cells, and that non-transformed thyroid cells are significantly less affected by this compound. Surprisingly, we show that Obatoclax rapidly localizes to the lysosomes and induces loss of acidification, block of lysosomal fusion with autophagic vacuoles, and subsequent lysosomal permeabilization. Notably, prior lysosome neutralization using different V-ATPase inhibitors partially protects cancer cells from the toxic effects of Obatoclax. Although inhibition of autophagy does not affect Obatoclax-induced cell death, selective down-regulation of ATG7, but not of ATG5, partially impairs Obatoclax effects, suggesting the existence of autophagyindependent functions for ATG7. Strikingly, Obatoclax killing activity depends only on its accumulation in the lysosomes, and not on its interaction with BCL2 family members. Finally, we show that also other lysosome-targeting compounds, Mefloquine and LLOMe, readily induce necrosis in thyroid cancer cells, and that Mefloquine significantly impairs tumor growth in vivo, highlighting a clear vulnerability of these aggressive, apoptosis-resistant tumors that can be therapeutically exploited.

Original languageEnglish (US)
Pages (from-to)34453-34471
Number of pages19
JournalOncotarget
Volume7
Issue number23
DOIs
StatePublished - Jun 7 2016

Fingerprint

Lysosomes
Necrosis
Thyroid Neoplasms
Mefloquine
Neoplasms
Cell Death
Apoptosis
Apoptosis Regulatory Proteins
Poisons
Autophagy
Growth
Vacuoles
Anaplastic Thyroid Carcinoma
obatoclax
Adenosine Triphosphatases
Thyroid Gland
Down-Regulation

Keywords

  • Autophagy
  • Lysosomes
  • Necrosis
  • Obatoclax
  • Thyroid cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. / Champa, Devora; Orlacchio, Arturo; Patel, Bindi; Ranieri, Michela; Shemetov, Anton; Verkhusha, Vladislav; Cuervo, Ana Maria; Di Cristofano, Antonio.

In: Oncotarget, Vol. 7, No. 23, 07.06.2016, p. 34453-34471.

Research output: Contribution to journalArticle

Champa, Devora ; Orlacchio, Arturo ; Patel, Bindi ; Ranieri, Michela ; Shemetov, Anton ; Verkhusha, Vladislav ; Cuervo, Ana Maria ; Di Cristofano, Antonio. / Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis. In: Oncotarget. 2016 ; Vol. 7, No. 23. pp. 34453-34471.
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