Syntaphilin Is a Novel Biphasic Biomarker of Aggressive Prostate Cancer and a Metastasis Predictor.

Easily accessible biomarkers that may inform on the metastatic potential of localized prostate cancer are urgently needed. Herein, we show that syntaphilin (SNPH), a molecule originally identified as a negative regulator of mitochondrial dynamics in neurons, is abundantly expressed in prostate cancer. SNPH distribution in prostate cancer is spatially biphasic, with high expression at the invasive front, correlating with increased proliferative rates, as determined by Ki-67 labeling, and reduced levels in the central tumor bulk, which are further decreased in patients with distant metastases.

A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy.

Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π contacts and hydrophobic interactions with the surrounding amino acids in the active site.

A neuronal network of mitochondrial dynamics regulates metastasis.

The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo.

Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development.

Protein homeostasis, or proteostasis, is required for mitochondrial function, but its role in cancer is controversial. Here we show that transgenic mice expressing the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) in the prostate develop epithelial hyperplasia and cellular atypia. When examined on a Pten background, a common alteration in human prostate cancer, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten mice without affecting hyperplasia or prostatic intraepithelial neoplasia.

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming.

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia.

Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug.

Increasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1(+/+) versus Cav-1(-/-) age-matched young female mice).

Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate.

Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors.

Using Caveolin-1 epithelial immunostaining patterns to stratify human breast cancer patients and predict the Caveolin-1 (P132L) mutation.

Caveolin-1 (Cav-1) mutations, such as P132L, are associated with ER-positive human breast cancers. However, no immunohistochemical methods have yet been described to predict the presence of Cav-1 mutations in human breast cancer. Since the P132L mutation acts in a dominant-negative fashion and causes the mis-localization of Cav-1 in cultured cells in vitro, we hypothesized that of patients carrying this mutation would show a similar Cav-1 staining pattern in vivo.

Genetic ablation of caveolin-1 drives estrogen-hypersensitivity and the development of DCIS-like mammary lesions.

Caveolin-1 (Cav-1) loss-of-function mutations are exclusively associated with estrogen receptor-positive (ER(+)) human breast cancers. To dissect the role of Cav-1 loss-of-function in the pathogenesis of human breast cancers, we used Cav-1(-/-) null mice as a model system. First, we demonstrated that Cav-1(-/-) mammary epithelia overexpress two well-established ER co-activator genes, CAPER and Foxa1, in addition to ER-alpha.