Tumor metastasis is the primary culprit of prostate cancer (PCa) lethality, representing the second most frequent cause of cancer death in men. The loss of epithelial polarity, maintained via junctional proteins and the apicobasal (a/b) polariy network, is a major risk factor for tumor progression and metastasis. There is a significant gap in knowledge regarding the initiating signaling events that destabilize cell polarity in PCa. We now demonstrate that tumor secreted extracellular Hsp90 (eHsp90) profoundly alters cellular polarization by initiating an interconnected cascade of molecular events. The goal of this proposal is to identify the molecular mechanisms by which eHsp90 subverts epithelial polarity to support invasive behavior and PCa progression. We find that eHsp90 sustains MEK/ERK signaling, a trend conserved in aggressive models of PCa. This eHsp90-MEK/ERK pathway subsequently impacts upon several components of Wnt signaling to induce Wnt//?-catenin activation. These molecular observations are functionally relevant, as MEK/ERK and ?-catenin participate in eHsp90's destabilization of cell polarity. Moreover, eHsp90 action couples to ZEB1, a transcription factor that potently suppresses epithelial polarity in part via targeting proteins associated with the polarity network. ZEB1 and its antagonistic microRNA miR-200 engage in a reciprocal feedback loop, functioning as a pivotal control module for epithelial plasticity. We posit that the ZEB1-miR-200 axis is a major effector for eHsp90's disruption of cell polarity, as supported by molecular trends in primary patient PCa specimens. We will test the premise that eHsp90-mediated signaling events recalibrate the ZEB1-miR-200 axis, resulting in ZEB1-mediated suppression of essential proteins required for maintenance of the polarity network. Collectively, our provocative findings support the premise that eHsp90 plays a previously unappreciated role as a central regulator of the polarity network. The proposed study will dissect the molecular events contributing to eHsp90's loss of polarity, and will establish whether diminished fidelity of the polarity network is a requisite for eHsp90's invasive behavior. The elucidation of key signaling and molecular effectors of eHsp90 action is expected to yield an expanded repertoire of pharmacological opportunities aimed at functional restoration of the polarity network to antagonize or pre-empt cancer invasion and metastasis. Moreover, these trends may serve as a molecular fingerprint to identify early stage tumors at greater risk for progression.

Public Health Relevance

Prostate cancer remains the second most lethal male malignancy. Distinguishing lethal tumors from the indolent majority is a major clinical challenge. Tumor invasion is a risk factor for progression, and loss of epithelial polarity is associated with both of these processes. Therefore, understanding the initiating signaling events that compromise cell polarity in PCa may create therapeutic opportunities to antagonize or pre-empt cancer invasion and metastasis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA187342-01
Application #
8749937
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29403