Background: Metastatic prostate cancer express laminin binding integrins α6 and α3 while losing the expression of a variety of integrins present in normal prostate gland.

Results: In human xenograft tissues, at least 70% of bone and soft tissue metastasis of prostate cancer (185 samples from 45 patients) had cytoplasmic expression of the α6 integrin that correlated to increased expression of intracellular trafficking proteins. Given the reported link between cytoplasmic integrin distribution and integrin endocytosis, surface labelled integrin α6 were quantified for internalization kinetics using flow cytometry. The integrin α6 was internalized 3-fold faster than α3 integrin (CD49c) (1.0 min-1), 1.5-fold faster than the vitronectin binding αv integrin (CD51) (2.2 min-1), and significantly slower than the unrelated transferrin receptor (TfR, CD71) (15 min-1).

Silencing α3 expression increased α6 integrin internalization by 1.45 fold without affecting internalization of non-integrin control receptor, TfR. The internalized α6 integrin was targeted to early endosomes and Rab4 recycling vesicles and redistributed to a cell-cell staining pattern similar to human prostate cancer specimens. This was accompanied by a 1.8-fold increase in cancer cell migration that was dependent on α6 integrin. Silencing integrin α6 however, didn't affect the internalization rate or intracellular endocytic distribution of the α3 integrin.

Conclusion and Significance: We conclude that internalization of the α6 and α3 integrins is coordinated in a unidirectional fashion and their relative expression can significantly modulate cancer cell migration. The observed loss of α3 integrin expression in high grade cancer is predicted to increase the internalization and pro-migratory features of α6 integrin in high grade cancer.

Acknowledgements: Research was supported in part by NIH research grants R01 CA 159406, CA 23074 and CA09213. Patient tissue studies were supported by Biobank and Translational Research Core, Cedars Sinai Medical Center, CA, Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grants (PO1CA085859) and the Richard M. LUCAS Foundation.

Citation Format: Lipsa Das, Todd A. Anderson, Jaime M. Gard, Isis C. Sroka, Stephanie R. Strautman, Raymond B. Nagle, Colm Morrissey, Beatrice S. Knudsen, Anne E. Cress. Loss of α3 integrin expression promotes α6 integrin internalization to Rab4 vesicles and migration of human prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A60.