Extracellular Matrix Proteins Protect Pancreatic Cancer Cells From Death via Mitochondrial and Nonmitochondrial Pathways

Gastroenterology. 2003 Oct;125(4):1188-202. doi: 10.1016/s0016-5085(03)01203-4.

Abstract

Background and aims: Pancreatic cancer is a very aggressive malignancy. Normal cells die through apoptosis when detached from extracellular matrix (ECM), but the role of ECM in cancer cell survival is poorly understood. Here, we determined the effects of ECM proteins on death responses and underlying signaling pathways in human pancreatic cancer cells.

Methods: We measured apoptosis and necrosis, caspase activation, and mitochondrial dysfunction in MIA PaCa-2 and PANC-1 pancreatic carcinoma cells both detached and attached to ECM proteins.

Results: Detachment of pancreatic cancer cells from ECM did not induce classic apoptosis, as it does in normal cells, but induced necrosis and apoptosis associated with secondary necrosis. It caused a pronounced mitochondrial depolarization and release of cytochrome c and Smac/DIABLO. However, as different from normal cells, cytochrome c release did not result in downstream caspase activation. Executioner caspases were activated in detached pancreatic cancer cells independent of cytochrome c. Laminin and fibronectin, but not collagen I, markedly increased pancreatic cancer cell survival by inhibiting both mitochondrial dysfunction (leading to inhibition of necrosis) and caspase activity (leading to decreased apoptotic DNA fragmentation).

Conclusions: ECM proteins greatly protect pancreatic cancer cells from death by mechanisms different from those operating in normal cells. The results suggest ECM proteins and their receptors as potential targets for treatment of pancreatic cancer.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Carcinoma, Pancreatic Ductal*
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Collagen Type I / pharmacology
  • Cytochrome c Group / metabolism
  • Extracellular Matrix Proteins / pharmacology*
  • Fibronectins / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Laminin / pharmacology
  • Mitochondria / enzymology*
  • Mitochondrial Proteins / metabolism
  • Necrosis
  • Pancreatic Neoplasms*
  • Polyamines / pharmacology
  • Polyhydroxyethyl Methacrylate / analogs & derivatives*
  • Polyhydroxyethyl Methacrylate / pharmacology
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Collagen Type I
  • Cytochrome c Group
  • DIABLO protein, human
  • Extracellular Matrix Proteins
  • Fibronectins
  • Intracellular Signaling Peptides and Proteins
  • Laminin
  • Mitochondrial Proteins
  • Polyamines
  • poly(2-hydroxyethyl methacrylate)-polyamine graft copolymer
  • Polyhydroxyethyl Methacrylate
  • Caspases