Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells

Abstract

Resveratrol, a polyphenol found in grapes and other fruit and vegetables, is a powerful chemopreventive and chemotherapeutic molecule potentially of interest for the treatment of breast cancer. The human breast cancer cell line MCF-7, which is devoid of caspase-3 activity, is refractory to apoptotic cell death after incubation with resveratrol. Here we show that resveratrol arrests cell proliferation, triggers death and decreases the number of colonies of cells that are sensitive to caspase-3-dependent apoptosis (MCF-7 casp-3 ) and also those that are unresponsive to it (MCF-7 vc ). We demonstrate that resveratrol (i) acts via multiple pathways to trigger cell death, (ii) induces caspase-dependent and caspase-independent cell death in MCF-7 casp-3 cells, (iii) induces only caspase-independent cell death in MCF-7 vc cells and (iv) stimulates macroautophagy. Using BECN1 and hVPS34 (human vacuolar protein sorting 34) small interfering RNAs, we demonstrate that resveratrol activates Beclin 1-independent autophagy in both cell lines, whereas cell death via this uncommon form of autophagy occurs only in MCF-7 vc cells. We also show that this variant form of autophagic cell death is blocked by the expression of caspase-3, but not by its enzymatic activity. In conclusion, this study reveals that non-canonical autophagy induced by resveratrol can act as a caspase-independent cell death mechanism in breast cancer cells.

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

“…Beclin-1-independent pathways of autophagy are being elucidated. 39 We suggest that in nonHodgkin lymphomas not expressing beclin-1 the chemotherapy regimen should include drugs able to induce beclin-1-independent autophagy. Finally, the data here reported show that the immunohistochemical detection of beclin-1 (and of LC3) in nonHodgkin lymphoma has a great prognostic potential.…”

“…In a few cases, tumours with a low percentage of beclin-1-positive cells presented with a relative high proportion of LC-3-positive cells, which is suggestive of the activation of a beclin-1-independent autophagy pathway. 39 Although the number of cases examined for LC3-positivity was relatively small (36 cases), and despite they were arbitrarily chosen as representative of the whole series, the data obtained indicate (1) that beclin-1 macro-aggregates associate with functional autophagy (as assessed by vacuolar LC3-positivity) in the majority of the cases (71%), and (2) that upregulation of autophagy (assumed as X20% LC3-positive cells) in the tumour context associates with a favourable outcome.…”

Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

“…19 Also, downregulation of BECN1 with sh-BECN1 inhibited autophagy in MCF-7 cells. 17,19,[40][41][42] Although it is debatable whether BAF inhibits the fusion of autophagosomes and lysosomes, BAF is still used as an inhibitor to study autophagic flux in many studies. 43 Recently, Shingu et al reported that imatinib, a drug of molecular targeted therapy, induced autophagy in human malignant glioma cells.…”

Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function

“…Amongst the autophagy genes, beclin-1/ATG6 is a key initiator of autophagy in mammalian cells Cao and Klionsky, 2007), although it may be bypassed under certain conditions (Chu et al, 2007;Scarlatti et al, 2008). Beclin-1 was first identified as a protein that interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL, but not with Bax/Bak (Liang et al, 1998), and classified recently as a BH3-only protein (Oberstein et al, 2007;Maiuri et al, 2007b).…”