Is autophagy rather than apoptosis the regression driver in imatinib-treated gastrointestinal stromal tumors?

Francesca Miselli, Tiziana Negri, Alessandro Gronchi, Marco Losa, Elena Conca, Silvia Brich, Elena Fumagalli, Marco Fiore, Paolo G. Casali, Marco A. Pierotti, Elena Tamborini, Silvana Pilotti

Research output: Contribution to journalArticle

Abstract

Although apoptosis (programmed cell death type I) is more frequently reported in the literature in imatinib-treated gastrointestinal stromal tumor (GIST) cell lines, morphological features consistent with autophagic changes aremore often encountered in surgical specimens of treated patients. Autophagy (programmed cell death type II) is highly regulated by a tumor-suppressor mechanism that mainly involves the genes beclin1, PI3KIII, and bcl2. Being our material not suitable for electron microscopy analysis (not paraformaldehyde-glutaraldehyde-fixed), we evaluated the morphological, biochemical, and immunophenotypical profiles expected to be related to autophagy and apoptosis in a series of surgically resected samples taken from 11 imatinib-treated patients with molecularly characterized GISTs. The samples were examined for imatinib-induced morphological changes, the presence/interactions of the autophagic-related proteins (beclin1, PI3KIII, bcl2, and LC3-II) and the presence of apoptosis-related proteins (caspase 3, caspase 7, and lamin A/C) by means ofWestern blot analysis and coimmunoprecipitation, complemented by immunohistochemistry. We also studied samples of two untreated GISTs used as controls. Sampling areas with different residual cellularity scores fromboth the imatinib-treated and untreated patients showed biochemical and immunohistochemical evidence of high levels of proautophagy beclin1/PI3KIII and low levels of antiautophagy beclin1/bcl2 complexes, together with the presence of LC3-II detected by Western blot analysis, thus supporting the presence of autophagy. There was no expression of cleaved/activated caspase 3 or 7 or cleaved lamin A/C. Our descriptive results support the idea that GISTs activate autophagy rather than apoptosis in response to imatinib treatment and that their molecular makeup includes fingerprints of autophagy.

Original languageEnglish
Pages (from-to)177-186
Number of pages10
JournalTranslational Oncology
Volume1
Issue number4
DOIs
Publication statusPublished - Nov 2008

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Gastrointestinal Stromal Tumors
Autophagy
Apoptosis
Lamin Type A
Caspase 7
Caspase 3
Dermatoglyphics
Glutaral
Stromal Cells
Tumor Cell Line
Imatinib Mesylate
Electron Microscopy
Proteins
Western Blotting
Immunohistochemistry
Beclin-1
Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Is autophagy rather than apoptosis the regression driver in imatinib-treated gastrointestinal stromal tumors? / Miselli, Francesca; Negri, Tiziana; Gronchi, Alessandro; Losa, Marco; Conca, Elena; Brich, Silvia; Fumagalli, Elena; Fiore, Marco; Casali, Paolo G.; Pierotti, Marco A.; Tamborini, Elena; Pilotti, Silvana.

In: Translational Oncology, Vol. 1, No. 4, 11.2008, p. 177-186.

Research output: Contribution to journalArticle

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