AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor.
The regulation of the subcellular localization of phosphatase and tensin homologue (PTEN) is critical to its tumor-suppressing functions. Previously, we found that the activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR/S6 protein kinase (S6K) cascade triggers the nuclear export of PTEN during the G1/S transition. Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5' adenosine monophosphate-activated protein kinase (AMPK), we proposed that the activation of AMPK α1/2 by LKB1 and/or by calmodulin-dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K. We found that in LKB1-null A549 lung adenocarcinoma cells, an AMPK activator, metformin, failed to block the nuclear export of PTEN, and the reintroduction of functional LKB1 into these cells restored the metformin-mediated inhibition of the nuclear export of PTEN. In addition, the nuclear export of PTEN was blocked in cells treated with the CaMKK activator ATP, and this inhibition was reversed by the addition of inhibitors of either AMPK (compound C) or CaMKK (STO-609). Although the nuclear export of PTEN is blocked by metformin in MCF-7 breast cancer cells carrying wild-type LKB1, this inhibition could not be reversed by an AMPK inhibitor, suggesting that LKB1 could regulate the nuclear export of PTEN by bypassing AMPK α1/2. Moreover, ATP could not block the nuclear export of PTEN in AMPK α1/2(-/-) or TSC2(-/-) mouse embryonic fibroblasts. However, metformin was still able to induce the LKB1-mediated inhibition of the nuclear export of PTEN in these cells. Taken together, these findings strongly suggest that although CaMKK mediates the nuclear retention of PTEN mainly through the activation of AMPK, LKB1 can regulate the nuclear-cytoplasmic trafficking of PTEN, with or without the AMPK/TSC2/mTOR/S6K-signaling intermediates.
Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Juinn-Lin
JL
Liu
Zhenyu
Z
Mao
Gary E
GE
Gallick
W K Alfred
WK
Yung
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D007004:Hypoglycemic Agents; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D008687:Metformin; C546842:MTOR protein, human; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human