Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage.
Among the cellular responses to photodamage initiated by photodynamic therapy (PDT) are autophagy and apoptosis. While autophagy is a reversible process that can be both a survival and a death pathway, apoptosis is irreversible, leading only to cell death. In this study, we followed the fate of mouse leukemia L1210 cells after photodamage to the endoplasmic reticulum (ER) using a porphycene photosensitizer, where Bcl-2 was among the PDT targets. In wild-type cells, we observed a rapid wave of autophagy, presumed to represent the recycling of some damaged organelles, followed by apoptosis. Using shRNA technology, we created a Bax knockdown line (L1210/Bax(-)). In the latter cell line, we found a marked decrease in apoptosis after photodamage or pharmacologic inactivation of Bcl-2 function, but this did not affect PDT efficacy. Loss of viability was associated with a highly-vacuolated morphology consistent with autophagic cell death. Previous studies indicated pro-survival attributes of autophagy after low-dose PDT, suggesting that autophagy may be responsible for the 'shoulder' on the dose-response curve. It appears that attempts at extensive recycling of damaged organelles are associated with cell death, and that this phenomenon is amplified when apoptosis is suppressed.
Kessel
David
D
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Arroyo
Adelaida Segarra
AS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D017353:Gene Deletion; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010778:Photochemotherapy / Q000009:adverse effects*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D013997:Time Factors
C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; C051407:porphycene; D000071193:Autophagy-Related Protein 7