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Review
. 2015 Dec 15;6(40):42603-12.
doi: 10.18632/oncotarget.6058.

The double face of Morgana in tumorigenesis

Mara Brancaccio  1 , Stefania Rocca  1 , Laura Seclì  1 , Elena Busso  1 , Federica Fusella  1
Affiliations
Review

The double face of Morgana in tumorigenesis

Mara Brancaccio et al. Oncotarget. .

Abstract

Morgana is a chaperone protein able to bind to ROCK I and II and to inhibit their kinase activity. Rho kinases are multifunctional proteins involved in different cellular processes, including cytoskeleton organization, centrosome duplication, cell survival and proliferation. In human cancer samples Morgana appears to be either downregulated or overexpressed, and experimental evidence indicate that Morgana behaves both as an oncosuppressor and as a proto-oncogene. Our most recent findings demonstrated that if on the one hand low Morgana expression levels, by inducing ROCK II hyperactivation, cause centrosome overduplication and genomic instability, on the other hand, Morgana overexpression induces tumor cell survival and chemoresistance through the ROCK I-PTEN-AKT axis. Therefore, Morgana belongs to a new class of proteins, displaying both oncogenic and oncosuppressor features, depending on the specific cellular context.

Keywords: Morgana; ROCK; atypical chronic myeloid leukemia; chemoresistance; chord containing protein.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Morgana structure
Schematic representation of Morgana structure. The protein is characterized by two tandemly repeated CHORD domains (CHORD1 and CHORD2) and a C-terminal CS domain.
Figure 2
Figure 2. Signal transduction in CML expressing normal Morgana levels
CML is caused by the presence of constitutive active kinase Bcr/Abl that leads to the hyperactivation of several signaling pathways, including PI3K, ROCK, MAPK and JAK-STAT signaling pathways [39], enhancing proliferation and survival (on the left). CML cells are addicted to Bcr/Abl signaling and Bcr/Abl inhibition using imatinib, induces apoptosis in these cells (on the right).
Figure 3
Figure 3. Overview of atypical CML
Atypical CML bone marrow cells underexpressing Morgana are characterized by high ROCK activity which sustains survival of these cells establishing a mechanism of oncogene addiction (on the left). In fact, when ROCK is pharmacologically inhibited using fasudil, these cells can no longer survive and undergo apoptosis (on the right).
Figure 4
Figure 4. Signal transduction in CML cells expressing low Morgana levels
In CML cells Bcr/Abl activates ROCK inducing addiction to its signaling and enhancing cell proliferation and survival. Morgana low expression levels cooperate with Bcr/Abl signaling to further increase ROCK activity. Consequently, low Morgana patients exhibit a sub-optimal response to imatinib (on the left). Using a combined treatment of imatinib and the ROCK inhibitor fasudil, the apoptotic response of low Morgana CML cells is restored (on the right).
Figure 5
Figure 5. Schematic representation of Morgana normal and Morgana overexpressing breast cancer cells
When breast cancer cells expressing normal Morgana levels are subjected to an apoptotic stimulus, they undergo apoptosis (on the right). Morgana overexpression, inhibiting ROCK activity, causes decreased PTEN stability and, in turn, increased AKT phosphorylation, responsible for cancer cells survival and chemoresistance (on the left).
Figure 6
Figure 6. The importance of balancing Morgana levels
In tumor cells Morgana low expression levels enhance ROCK activity, inducing proliferation, survival and genomic instability. ROCK inhibitors may be used as a new therapeutic approach able to rescue low Morgana levels in tumor cells (on the left). On the other hand, Morgana overexpression reduces ROCK activity and PTEN stability, enhancing AKT activation. As a consequences, Morgana high expressing cells are resistant to chemotherapy. In this context, AKT inhibitors can represent a promising approach to restore chemosensitivity (on the right).
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