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Beck TN , Korobeynikov VA , Kudinov AE , Georgopoulos R , Solanki NR , Andrews-Hoke M , Kistner TM , Pepin D , Donahoe PK , Nicolas E , Einarson MB , Zhou Y , Boumber Y , Proia DA , Serebriiskii IG , Golemis EA
Anti-Mullerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer
Cell Rep. 2016 Jul 19;16(3) :657-71
PMID: 27396341    PMCID: PMC4956518   
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Abstract
Anti-Mullerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-beta)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-beta/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor kappaB (AKT-NF-kappaB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-beta/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT.
Notes
Beck, Tim N Korobeynikov, Vladislav A Kudinov, Alexander E Georgopoulos, Rachel Solanki, Nehal R Andrews-Hoke, Magda Kistner, Timothy M Pepin, David Donahoe, Patricia K Nicolas, Emmanuelle Einarson, Margret B Zhou, Yan Boumber, Yanis Proia, David A Serebriiskii, Ilya G Golemis, Erica A F30 CA180607/CA/NCI NIH HHS/United States P50 CA083638/CA/NCI NIH HHS/United States R21 CA181287/CA/NCI NIH HHS/United States R21 CA191425/CA/NCI NIH HHS/United States United States Cell Rep. 2016 Jul 19;16(3):657-71. doi: 10.1016/j.celrep.2016.06.043. Epub 2016 Jul 7.