Understanding and targeting PI3K downstream of oncogenic Met mutant
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The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a
major role in cancer progression and represents an attractive target for cancer therapy.
This study aimed to investigate whether PI3K plays a role in Met oncogenicity.
Three cell models were used: (i) NIH3T3 cells expressing WT Met or the constitutively
active mutant M1268T Met; (ii) U87MG glioblastoma cells, with endogenous WT Met
constitutively activated due to an autocrine loop; (iii) A549 lung cancer cells expressing
endogenous WT Met, activated upon binding exogenous HGF.
Met dependent Rac1 translocation to the plasma membrane, actin cytoskeleton
organisation, cell migration, anchorage independent growth in soft agar and tumour
growth were studied in the presence of inhibitors of pan-PI3K / mTOR, various PI3K
Class I isoforms, mTOR or Akt, or following siRNA knock-down of PI3K isoforms.
We report that PI3K class I (but not class III) regulates Met dependent cell migration.
The PI3K class I isoforms required varies among the cell models. Interestingly, the
combined inhibition of all p110 Class I isoforms lead to the strongest reduction of Met
dependent cell migration. Met dependent phosphorylation of Akt, an effector of PI3K
class I, is reduced upon endocytosis inhibition, suggesting that Met signals to PI3K
Class I on endosomes.
Our results indicate that mTOR is responsible for Met dependent anchorage
independent growth and tumour growth in vivo. Surprisingly, PI3K class I (and class
III) are not required. Moreover, Rac1 is required for Met dependent mTOR activation,
(phosphorylation of mTORC1’s effector, p70 S6K) subcellular translocation of mTOR
and anchorage independent growth. Finally, our results suggest that this Met-Rac1-
mTOR pathway occurs on endosomes.
Thus while PI3K class I regulates Met dependent cell migration, mTOR regulates Met
driven anchorage independent growth and in vivo tumorigenesis. Thus PI3K Class I /
mTOR may be targeted in Met driven cancers.
Authors
Hervieu Vilches, AlexiaCollections
- Theses [4122]