Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors.
BACKGROUND
Prostate cancer (CaP) progression from an androgen-dependent to an androgen-independent state is associated with overexpression of EGFR family members or activation of their downstream signaling pathways, such as PI3K-Akt and MAPK. Although there are data implicating PI3K-Akt or MAPK pathway activation with resistance to EGFR inhibitors in CaP, the potential cross-talk between these pathways in response to EGFR or MAPK inhibitors remains to be examined.


METHODS
Cross-talk between PTEN and MAPK signaling and its effects on CaP cell sensitivity to EGFR or MAPK inhibitors were examined in a PTEN-null C4-2 CaP cell, pTetOn PTEN C4-2, where PTEN expression was restored conditionally.


RESULTS
Expression of PTEN in C4-2 cells exposed to EGF or serum was associated with increased phospho-ERK levels compared to cells without PTEN expression. Similar hypersensitivity of MAPK signaling was observed when cells were treated with a PI3K inhibitor LY294002. This enhanced sensitivity of MAPK signaling in PTEN-expressing cells was associated with a growth stimulatory effect in response to EGF. Furthermore, EGFR inhibitors gefitinib and lapatinib abrogated hypersensitivity of MAPK signaling and cooperated with PTEN expression to inhibit cell growth in both monolayer and anchorage-independent conditions. Similar cooperative growth inhibition was observed when cells were treated with the MEK inhibitor, CI1040, in combination with PTEN expression suggesting that inhibition of MAPK signaling could mediate the cooperation of EGFR inhibitors with PTEN expression.


CONCLUSIONS
Our results suggest that signaling cross-talk between the PI3K-Akt and MAPK pathways occurs in CaP cells, highlighting the potential benefit of targeting both the PI3K-Akt and MAPK pathways in CaP treatment.
Wu
Z
Z
Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
Gioeli
D
D
Conaway
M
M
Weber
M J
MJ
Theodorescu
D
D
D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology
D001549:Benzamides; D002867:Chromones; D066246:ErbB Receptors; D000077156:Gefitinib; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human