Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways
Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.
KeywordsGlypican-3 Apoptosis PI3K/Akt pathway p38MAPK pathway Breast cancer
We would like to give our thanks to Guillermo Peluffo for technical assistance and to Dr. Mariana Salatino for her invaluable assistance in responding the reviewer requests. The work was supported by grants from FONCyT (PICT 14088, Préstamo BID 1728/OC-AR; PICT 00220, Préstamo BID 1728/OC-AR) and from the University of Buenos Aires (UBACyT M068).
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