Ca(2+) signaling is important to trigger the cell cycle progression, while it remains elusive in the regulatory mechanisms. Here we show that store-operated Ca(2+) entry (SOCE), mediated by the ...interaction between STIM1 (an endoplasmic reticulum Ca(2+) sensor) and Orai1 (a cell membrane pore structure), controls the specific checkpoint of cell cycle. The fluctuating SOCE activity during cell cycle progression is universal in different cell types, in which SOCE is upregulated in G1/S transition and downregulated from S to G2/M transition. Pharmacological or siRNA inhibition of STIM1-Orai1 pathway of SOCE inhibits the phosphorylation of CDK2 and upregulates the expression of cyclin E, resulting in autophagy accompanied with cell cycle arrest in G1/S transition. The subsequently transient expression of STIM1 cDNA in STIM1(-/-) MEF rescues the phosphorylation and nuclear translocation of CDK2, suggesting that STIM1-mediated SOCE activation directly regulates CDK2 activity. Opposite to the important role of SOCE in controlling G1/S transition, the downregulated SOCE is a passive phenomenon from S to G2/M transition. This study uncovers SOCE-mediated Ca(2+) microdomain that is the molecular basis for the Ca(2+) sensitivity controlling G1/S transition.
The remodeling of Ca
homeostasis has been implicated as a critical event in driving malignant phenotypes, such as tumor cell proliferation, motility, and metastasis. Store-operated Ca
entry (SOCE) ...that is elicited by the depletion of the endoplasmic reticulum (ER) Ca
stores constitutes the major Ca
influx pathways in most nonexcitable cells. Functional coupling between the plasma membrane Orai channels and ER Ca
-sensing STIM proteins regulates SOCE activation. Previous studies in the human breast, cervical, and other cancer types have shown the functional significance of STIM/Orai-dependent Ca
signals in cancer development and progression. This article reviews the information on the regulatory mechanisms of STIM- and Orai-dependent SOCE pathways in the malignant characteristics of cancer, such as proliferation, resistance, migration, invasion, and metastasis. The recent investigations focusing on the emerging importance of SOCE in the cells of the tumor microenvironment, such as tumor angiogenesis and antitumor immunity, are also reviewed. The clinical implications as cancer therapeutics are discussed.
Dianellaensifolia is a perennial herb with thickened rhizome and is widely distributed in tropical and subtropical regions of Asia, Australia, and the Pacific islands. This plant has the potential to ...be used as a source of herbal medicine. This study investigated further phytochemistry and tyrosinase inhibitory effect of some constituents isolated from D. ensifolia. Four new flavans, (2S)-4'-hydroxy-6,7-dimethoxyflavan (1), (2S)-3',4'-dihydroxy-7-methoxy-8-methylflavan (2), (2S)-2'-hydroxy-7-methoxyflavan (3), and (2S,1′S)-4-hydroxy-4-(7-methoxy-8-methylchroman-2-yl)-cyclohex-2-enone (4), together with 67 known compounds, including 10 flavans (5-14), 5 flavanones (15-19), 3 flavone (20-22), 5 chalcones (23-27), 3 chromones (28-30), 15 aromatics (31-45), 7 phenylpropanoids (46-52), one lignan (53), 7 steroids (54-60), one monoterpene (61), one diterpene (62), 4 triterpenes (63-66), a carotenoid (67), 2 alkaloids (68 and 69), and 2 fatty acids (70 and 71) were isolated from D. ensifolia. Their structures were elucidated on the basis of physical and spectroscopic data analyses. Moreover, compounds 1-4, 8, 10-15, 20, 21, and 41 were evaluated for their mushroom tyrosinase inhibitory effect. Compounds 11 and 14 strongly inhibited mushroom tyrosinase activity with ICsub.50 values of 8.6 and 14.5 μM, respectively.
The clinical significance of STIM proteins and Orai Ca
channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that ...facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca
signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca
entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1
) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca
microdomain that is the molecular basis for Ca
sensitivity controlling podosome formation.
The mold
Monascus
has been used as a natural food coloring agent and food additive for more than 1000 years in Asian countries. In Chinese herbology, it was also used for easing digestion and ...antiseptic effects. Through a thorough investigation of a citrinin-free strain:
M. purpureus
BCRC 38110, four azaphilones, three benzenoids, one benzofuranone, one 5′,6′-dihydrospiroisochromane-1,2′-pyran-4′(3′
H
)-one derivative, two steroids, and six tetralones have been successfully identified. Among them, monapyridine A (
1
), monatetralones A-E (
2-6
), and monabenzofuranone (
7
) were first reported. Their structures were characterized by 1D and 2D NMR, UV, IR, and HRESIMS analyses. With a series of bioactivity screening, monascuspirolide B (
14
) and ergosterol peroxide (
16
) exhibited concentration-dependent attenuation of the paclitaxel-induced neurite damage of mouse dorsal root ganglion neurons. The interleukin (IL)-1β-induced release of inflammatory cytokines IL-8 and tumor necrosis factor (TNF)-α in human chondrosarcoma cells was inhibited by monapurpureusone (
8
) and monascuspirolide B (
14
). Altogether,
M. purpureus
BCRC 38110 possessed potentials as natural therapeutics against inflammatory osteoarthritis and paclitaxel-induced neurotoxicity.
Seven new and ten known compounds were isolated from a citrinin-free strain:
M. purpureus
BCRC 38110. The bioactivity results indicated that this strain possessed potentials against inflammatory osteoarthritis and paclitaxel-induced neurotoxicity.
The potassium chloride cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. Here, we investigate if KCC is involved in the regulation of ...epithelial-mesenchymal transition (EMT), a critical cellular event of malignancy. E-cadherin and {szligbeta}-catenin colocalize in the cell-cell junctions, which becomes more obvious in a time-dependent manner by blockade of KCC activity in cervical cancer SiHa and CaSki cells. Real-time reverse transcription-PCR on the samples collected from the laser microdissection indicates that KCC3 is the most abundant KCC isoform in cervical carcinoma. The characteristics of EMT appear in KCC3-overexpressed, but not in KCC1- or KCC4-overexpressed cervical cancer cells, including the elongated cell shape, increased scattering, down-regulated epithelial markers (E-cadherin and {szligbeta}-catenin), and up-regulated mesenchymal marker (vimentin). Some cellular functions are enhanced by KCC3 overexpression, such as increased invasiveness and proliferation, and weakened cell-cell association. KCC3 overexpression decreases mRNA level of E-cadherin. The promoter activity assays of various regulatory sequences confirm that KCC3 expression is a potent negative regulator for human E-cadherin gene expression. The proteosome inhibitor restores the decreased protein abundance of {szligbeta}-catenin by KCC3 overexpression. In the surgical specimens of cervical carcinoma, the decreased E-cadherin amount was accompanied by the increased KCC3 abundance. Vimentin begins to appear at the invasive front and becomes significantly expressed in the tumor nest. In conclusion, KCC3 down-regulates E-cadherin/{szligbeta}-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of {szligbeta}-catenin protein. The disruption of E-cadherin/{szligbeta}-catenin complex formation promotes EMT, thereby stimulating tumor progression. Cancer Res 2007; 67(22):11064-73
Insulin-like growth factor 1 (IGF-1) has been implicated in promoting mitogenic, metastatic and antiapoptotic phenotypes in several types of cancer. But little is known about the signal interaction ...of IGF-1 and integrin in the regulation of cervical cancer development and progression. This study is to investigate the regulatory mechanism of IGF-1 receptor (IGF-1R) signaling and its importance in cervical cancer formation. The growth and invasiveness of cervical cancer cells (SiHa and CaSki) were dose-dependently stimulated by IGF-1, whereas those of normal cervical epithelial cells were not. The immunoblot showed that IGF-1R proteins were abundant in cervical cancer cell lines. In contrast, IGF-1R protein was nearly undetectable in normal cervical epithelial cells. IGF-1-stimulated invasion and proliferation were abolished by functional-blocking monoclonal antibody against IGF-1R, whereas these cellular functions were unaffected by either IgG or monoclonal antibody to insulin receptor. Functional-blocking monoclonal antibody against integrins alpha sub(v) beta sub(3), but not alpha sub(2,) alpha sub(3), alpha sub(4,) alpha sub(6,) beta sub(1), beta sub(4) or alpha sub(2) beta sub(1), inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. alpha sub(v) beta sub(3) integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R. The modulation of alpha sub(v) beta sub(3) occupancy also affected the activation of IGF-1R downstream-signaling elements, including activation of Akt and extracellular signal-regulated protein kinases 1/2 (Erk1/2). The treatment of blocking antibody of alpha sub(v) beta sub(3) integrin or IGF-1R significantly inhibited tumor growth and caused tumor regression in SCID mice model. Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of alpha sub(v) beta sub(3) or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and alpha sub(v) beta sub(3) integrin plays an important role in promoting the development and progression of cervical cancer.
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