Inhibiting autophagy increases the efficacy of low-dose photodynamic therapy

Biochem Pharmacol. 2021 Dec:194:114837. doi: 10.1016/j.bcp.2021.114837. Epub 2021 Nov 12.


Rupture and permeabilization of endocytic vesicles can be triggered by various causes, such as pathogenic invasions, amyloid proteins, and silica crystals leading to cell death and degeneration. A cellular quality control process, called lysophagy was recently described to target damaged lysosomes for autophagic sequestration within isolation membranes in order to protect the cell from the consequences of lysosomal leakage. This protective process, however, might interfere with treatment conditions, such as photodynamic therapy (PDT) and the intracellular drug delivery method photochemical internalization (PCI). PCI-induced permeabilization of endosomes and lysosomes is purposely triggered to release drugs that are sequestered in these organelles into the cytosol in order to synergistically kill cancer cells. Here, we show that photochemical treatment with the PCI-photosensitizer TPCS2a/fimaporfin results in both induction of autophagy and inhibition of the autophagic flux. The autophagic response is accompanied by recruitment of ubiquitin (Ubq), p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3) to damaged vesicles, marked by Galectin 3 (Gal3). Furthermore, ultrastructural analysis revealed a homogenously thick p62-positive layer surrounding these permeabilized vesicles. Although p62 seems to be important during the selective autophagic sequestration, we show that its presence is not essential for the effective removal of damaged vesicles or the recovery of the lysosomal content. An active autophagic response and the presence of p62, however, is important for cancer cells to survive low-dose TPCS2a-PDT. Thus, targeting both p62 and autophagy together and independently, in a light-controlled/PCI based delivery of cancer therapeutics could increase the effectiveness of the treatment regime.

Keywords: Cell survival; Endo-lysosomal damage; FIP200; Photosensitizer; TPCS(2a); p62.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology*
  • Humans
  • Photochemotherapy / methods*
  • Photosensitizing Agents / pharmacology*
  • RNA-Binding Proteins / metabolism*
  • Treatment Outcome


  • P62 protein, human
  • Photosensitizing Agents
  • RNA-Binding Proteins