Abstract
Membrane hyaluronidase Hyal‐2 supports cancer cell growth. Inhibition of Hyal‐2 by specific antibody against Hyal‐2 or pY216‐Hyal‐2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal‐2. Alternatively, WWOX undergoes self‐polymerization and localizes in the cell membrane. Proapoptotic pY33‐WWOX binds Hyal‐2, and TGF‐β induces internalization of the pY33‐WWOX/Hyal‐2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14‐WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface‐exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3‐dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7‐21 peptide, or truncation to 5‐amino‐acid WWOX7‐11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time‐lapse microscopy revealed that WWOX7‐21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33‐WWOX, downregulation of prosurvival pERK, prompt increases in Ca+2 influx, and disruption of the IκBα/WWOX/ERK prosurvival signaling. In contrast, pS14‐WWOX7‐21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib‐mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14‐WWOX significantly enhanced the ceritinib‐induced apoptosis. Together, the N‐terminal epitopes WWOX7‐21 and WWOX7‐11 are potent in blocking cancer growth in vivo. WWOX7‐21 and WWOX7‐11 peptides and pS14‐WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.Support or Funding InformationMinistry of Science and Technology, Taiwan, National Health Research Institute, Taiwan, and Department of Defense, USAWWOX peptides regulate breast cancer cell sensitivity to ceritinib.Figure 1
Highlights
WW domain-containing oxidoreductase, known as WWOX, FOR and WOX1, was originally designated as a tumor suppressor protein [1,2,3,4,5,6]
We investigated the in vivo effects of WWOX peptides in controlling cancer growth
We examined whether WWOX peptides adhere to a specific protein(s) on cancer cell surface and Wesignal examined whether peptides adhere to a specific protein(s) cell surface and thereby for cancer cellWWOX
Summary
WW domain-containing oxidoreductase, known as WWOX, FOR and WOX1, was originally designated as a tumor suppressor protein [1,2,3,4,5,6]. WWOX is crucial in supporting neural development and differentiation. WWOX deficiency in newborns leads to the development of severe neural diseases, growth retardation, metabolic disorders, and early death [7,8,9,10,11]. WWOX gene is determined to be a risk factor for Alzheimer0 s disease (AD) [14]. In our recent report [15], we determined that p53 blocks WWOX-mediated inhibition of inflammatory immune response (e.g., splenomegaly) caused by cancer in vivo, which leads to protein aggregation in the brain such as in the AD. WWOX is considered as a tumor suppressor protein, WWOX-deficient human newborns do not spontaneously develop cancer [5,7,8]
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