Edick Mathew J, Tesfay Lia, Lamb Laura E, Knudsen Beatrice S, Miranti Cindy K
Laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Mol Biol Cell. 2007 Jul;18(7):2481-90. doi: 10.1091/mbc.e06-04-0261. Epub 2007 May 2.
In vivo in the prostate gland, basal epithelial cells adhere to laminin 5 (LM5) via alpha3beta1 and alpha6beta4 integrins. When placed in culture primary prostate basal epithelial cells secrete and adhere to their own LM5-rich matrix. Adhesion to LM5 is required for cell survival that is dependent on integrin-mediated, ligand-independent activation of the epidermal growth factor receptor (EGFR) and the cytoplasmic tyrosine kinase Src, but not PI-3K. Integrin-mediated adhesion via alpha3beta1, but not alpha6beta4 integrin, supports cell survival through EGFR by signaling downstream to Erk. PC3 cells, which do not activate EGFR or Erk on LM5-rich matrices, are not dependent on this pathway for survival. PC3 cells are dependent on PI-3K for survival and undergo caspase-dependent death when PI-3K is inhibited. The death induced by inhibition of EGFR or Src in normal primary prostate cells is not mediated through or dependent on caspase activation, but depends on the induction of reactive oxygen species. In addition the presence of an autophagic pathway, maintained by adhesion to matrix through alpha3beta1 and alpha6beta4, prevents the induction of caspases when EGFR or Src is inhibited. Suppression of autophagy is sufficient to induce caspase activation and apoptosis in LM5-adherent primary prostate epithelial cells.
在前列腺的体内环境中，基底上皮细胞通过α3β1和α6β4整合素与层粘连蛋白5（LM5）黏附。原代前列腺基底上皮细胞在培养时会分泌并黏附于自身富含LM5的基质。细胞存活需要与LM5黏附，这依赖于整合素介导的、不依赖配体的表皮生长因子受体（EGFR）和细胞质酪氨酸激酶Src的激活，但不依赖PI-3K。通过α3β1整合素介导的黏附（而非α6β4整合素），通过向Erk下游发出信号，经EGFR支持细胞存活。PC3细胞在富含LM5的基质上不激活EGFR或Erk，其存活不依赖此途径。PC3细胞的存活依赖PI-3K，当PI-3K被抑制时会发生半胱天冬酶依赖性死亡。在正常原代前列腺细胞中，抑制EGFR或Src诱导的死亡不是通过半胱天冬酶激活介导的，也不依赖于半胱天冬酶激活，而是依赖于活性氧的诱导。此外，通过α3β1和α6β4与基质黏附维持的自噬途径的存在，在EGFR或Src被抑制时可防止半胱天冬酶的诱导。自噬的抑制足以在黏附于LM5的原代前列腺上皮细胞中诱导半胱天冬酶激活和凋亡。
