MAP kinase pathways and calcitonin influence CD44 alternate isoform expression in prostate cancer cells.
BACKGROUND
Dysregulated expression and splicing of cell adhesion marker CD44 is found in many types of cancer. In prostate cancer (PC) specifically, the standard isoform (CD44s) has been found to be downregulated compared with benign tissue whereas predominant variant isoform CD44v7-10 is upregulated. Mitogen-activated protein kinase pathways and paracrine calcitonin are two common factors linked to dysregulated expression and splicing of CD44 in cancer. Calcitonin has been found to increase proliferation and invasion in PC acting through the protein kinase A pathway.


METHODS
In androgen-independent PC with known high CD44v7-10 expression, CD44 total and CD44v7-10 RNA or protein were assessed in response to exogenous and endogenous calcitonin and to inhibitors of protein kinase A, MEK, JNK, or p38 kinase. Benign cells and calcitonin receptor-negative PC cells were also tested.


RESULTS
MEK or p38 but not JNK reduced CD44 total RNA by 40%-65% in cancer and benign cells. Inhibition of protein kinase A reduced CD44 total and v7-10 protein expression. In calcitonin receptor-positive cells only, calcitonin increased CD44 variant RNA and protein by 3 h and persisting to 48 h, apparently dependent on an uninhibited p38 pathway. Cells with constitutive CT expression showed an increase in CD44v7-10 mRNA but a decrease in CD44 total RNA.


CONCLUSIONS
The MEK pathway increases CD44 RNA, while calcitonin, acting through the protein kinase A and p38 pathway, facilitates variant splicing. These findings could be used in the formulation of therapeutic methods for PC targeting CD44 alternate splicing.
Robbins
Eric W
EW
Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA. Eric.Robbins@UCHSC.edu
Travanty
Emily A
EA
Yang
Kui
K
Iczkowski
Kenneth A
KA
D017398:Alternative Splicing; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002116:Calcitonin / Q000494:pharmacology / Q000502:physiology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
D000951:Antigens, Neoplasm; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D002116:Calcitonin; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases
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