Integrins comprise a large family of cell surface receptors with critical roles in cancer cell proliferation, invasion and metastatic potential. Experiments carried out during the last funding cycle have uncovered a novel pathway of prostate cancer progression mediated by the av?6 integrin. We have found that av?6 is not expressed in human and mouse normal prostate but becomes significantly upregulated in preneoplastic lesions, prostatic adenocarcinoma (AdCa) and bone metastasis. Mechanistically, av?6 expression results in upregulation of androgen receptor (AR) activity via a JNK-mediated pathway. Our findings show, for the first time, that integrins modulate AR activity. In this pathway, we have identified survivin, a bifunctional regulator of cell division and inhibitor of apoptosis, as one of the critical downstream effector molecule which becomes upregulated in cells expressing av?6. Our in vivo data demonstrate that expression of av?6 results in enhanced tumor growth and metastatic dissemination as compared to a different av integrin, av?3. Expression of av?6 also causes tumor-mediated osteolysis, a crucial step in prostate cancer metastasis. Since av?3 has been shown to promote bone gain in prostate cancer metastatic lesions, we hypothesize that the extent of bone-lesion formation is controlled by the relative expression levels of av?6 and av?3. Finally, we show that these integrins'expression is regulated by two different transcription factors activated by TGF?: av?6 is induced via Smad3 activation, whereas av?3 expression is mediated by Runx2. We have formulated a unifying hypothesis that av?6 integrin functions as an integrator of multiple signaling pathways to promote early and late phases of prostate cancer progression. This hypothesis will be tested in the present renewal application by the following aims.
In Aim 1, the molecular mechanisms by which av?6 activates AR will be investigated.
In Aim 2, we will investigate in vivo the role of av?6 in prostate cancer progression in a mouse model of prostate cancer;for this purpose, we will use the prostate specific Pten-null mouse model which develops PIN, cancer and metastasis.
In Aim 3, to credential av integrins as molecular targets in prostate cancer bone lesion therapies, we will dissect the pathways by which av?6 and av?3 contribute to bone disease in vivo. Our long-term objective is to take advantage of this newly generated knowledge to develop novel molecular antagonists of prostate cancer progression.
|Wang, Tao; Huang, Jiayi; Vue, Mai et al. (2018) ?v?3 Integrin Mediates Radioresistance of Prostate Cancer Cells Through Regulation of Survivin. Mol Cancer Res :|
|Lu, Huimin; Bowler, Nicholas; Harshyne, Larry A et al. (2018) Exosomal ?v?6 integrin is required for monocyte M2 polarization in prostate cancer. Matrix Biol 70:20-35|
|Caino, M Cecilia; Seo, Jae Ho; Wang, Yuan et al. (2017) Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest 127:3755-3769|
|DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita et al. (2017) c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. J Cell Biochem 118:66-73|
|Lu, Huimin; Wang, Tao; Li, Jing et al. (2016) ?v?6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor. Cancer Res 76:5163-74|
|Sayeed, Aejaz; Lu, Huimin; Liu, Qin et al. (2016) ?1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation. Oncotarget 7:52618-52630|
|Chae, Young Chan; Vaira, Valentina; Caino, M Cecilia et al. (2016) Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming. Cancer Cell 30:257-272|
|Lisanti, Sofia; Garlick, David S; Bryant, Kelly G et al. (2016) Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development. J Biol Chem 291:25247-25254|
|Caino, M Cecilia; Seo, Jae Ho; Aguinaldo, Angeline et al. (2016) A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun 7:13730|
|Languino, Lucia R; Singh, Amrita; Prisco, Marco et al. (2016) Exosome-mediated transfer from the tumor microenvironment increases TGF? signaling in squamous cell carcinoma. Am J Transl Res 8:2432-7|
Showing the most recent 10 out of 53 publications