Publications by authors named "Xueliang Gao"

15 Publications

  • Page 1 of 1

Dihydroartemisinin alleviates high glucose-induced vascular smooth muscle cells proliferation and inflammation by depressing the miR-376b-3p/KLF15 pathway.

Biochem Biophys Res Commun 2020 09 1;530(3):574-580. Epub 2020 Aug 1.

Department of Urology, Hebei Hospital of Traditional Chinese Medicine, China. Electronic address:

Inflammation and the proliferation of vascular smooth muscle cells (VSMCs) are seen to play critical roles in the development of vascular complications induced by diabetes and hyperglycemia. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the effect of DHA on high glucose (HG)-induced inflammation and proliferation of VSMCs remains unknown. Therefore, this study aims to show that DHA significantly inhibited the proliferation of VSMCs and that expression of the inflammatory cytokines IL-1β and TNF-α was induced by HG in a dose-dependent manner. Additionally, we were able to determine that KLF15 played a critical role in HG-induced VSMC proliferation and inflammation, confirming its protective effects observed after DHA treatment in the HG-induced inflammatory response of VSMCs. DHA was observed to directly depress the HG-induced expression of miR-376b-3p, which targeted the 3'-UTR of KLF15 and inhibited its expression. These results suggested that DHA plays a protective role in HG-induced VSMC proliferation and associated inflammation by inhibiting the miR-376b-3p/KLF15 axis. Our findings provide new evidence of the mechanisms of DHA and its critical role in treating the pathogenesis of diabetic vascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.07.095DOI Listing
September 2020

Cyclin D-CDK4/6 functions in cancer.

Adv Cancer Res 2020 2;148:147-169. Epub 2020 Apr 2.

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.acr.2020.02.002DOI Listing
September 2020

High-speed 3D digital image correlation for rolling deformation of a tire sidewall and measuring dynamic contact patch length.

Appl Opt 2020 Feb;59(5):1313-1322

Tires play a vital role in a vehicle's operational stability, comfort, and security. However, due to the influence of test equipment and tire operating conditions, the perception of rolling tire characteristics is still in the stage of gradual improvement, especially the analysis of sidewall rolling deformation and dynamic contact peculiarities of tires/road interactions, which has restricted the analysis of rolling energy dissipation and the accurate observation of tire forces. In this paper, the high-speed stereo-vision system was created by high-speed cameras, and the relative rigid and flexible displacement, strain, and trajectory trend of marker points and the real-time global displacement field of the sidewall during the tire-rolling cycle were acquired utilizing the improved digital image correlation algorithm under different rolling velocities. Meanwhile, the periodic dissipation of the strain concentration region was observed, and the phenomenon of strain resonance appeared at the overlap of the periods. The relative flexibility strain and shear strain of the marker point were obtained on the plane element, which resulted in the relative flexibility major principle strain of the plane element, and then it achieved recognition of the leading and trailing points of the contact patch and the accurate measurement of dynamic contact patch length.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/AO.377604DOI Listing
February 2020

Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer.

Proc Natl Acad Sci U S A 2019 01 21;116(2):631-640. Epub 2018 Dec 21.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.

A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1808834116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329966PMC
January 2019

CRKL Mediates p110β-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells.

Cell Rep 2017 07;20(3):549-557

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.06.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704918PMC
July 2017

The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival.

Nature 2017 06 7;546(7658):426-430. Epub 2017 Jun 7.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature22797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516959PMC
June 2017

The phosphatidylinositol 3-kinase (PI3K) isoform dependence of tumor formation is determined by the genetic mode of PI3K pathway activation rather than by tissue type.

J Virol 2014 Sep 2;88(18):10673-9. Epub 2014 Jul 2.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

Unlabelled: Previous work has shown that prostate cancer in a Pten-null murine model is dependent on the p110β isoform of phosphatidylinositol 3-kinase (PI3K), while breast cancer driven by either polyoma middle T antigen (MT) or HER2 is p110α dependent. Whether these differences in isoform dependence arise from tissue specificity or from the nature of the oncogenic signal activating the PI3K pathway is important, given increasing interest in using isoform-specific PI3K inhibitors in cancer therapy. To approach this question, we studied the PI3K isoform dependence of our recently constructed prostate cancer model driven by MT. Since MT activates a number of signaling pathways, we first confirmed that the MT-driven prostate cancer model was actually dependent on PI3K. A newly generated transgenic prostate line expressing an MT allele (Y315F) known to be defective for PI3K binding displayed a markedly reduced ability to drive tumor formation. We next selectively ablated expression of either p110α or p110β in mice in which wild-type MT was expressed in the prostate. We found that tumor formation driven by MT was significantly delayed by the loss of p110α expression, while ablation of p110β had no effect. Since the tumor formation driven by MT is p110α dependent in the prostate as well as in the mammary gland, our data suggest that PI3K isoform dependence is driven by the mode of PI3K pathway activation rather than by tissue type.

Importance: Middle T antigen (MT), the oncogene of polyomavirus, can drive tumor formation in a variety of cell types and tissues. Interestingly, MT has no intrinsic enzymatic activity but instead functions by binding and activating cellular signaling proteins. One of the most important of these is the lipid kinase PI3K, which was first studied in MT immunoprecipitates. Ubiquitously expressed PI3K comes in two major isoforms: p110α and p110β. Previous work in animal models showed that p110α was the key isoform in breast tumors driven by oncogenes, including MT and HER2, while p110β was key in prostate tumors driven by Pten loss. We asked the simple question of whether a prostate tumor driven by MT depends on p110α, which would suggest that the mode of activation determines p110 isoform dependence, or p110β, which would suggest that tissue type determines isoform dependence. The clear answer is that MT depends on p110α in both the prostate and breast.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.01409-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178865PMC
September 2014

An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide).

Cancer Discov 2013 Sep 10;3(9):1030-43. Epub 2013 Jul 10.

1Oncology Disease Area, 2Department of Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge; and 3Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Unlabelled: Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR(F876L) confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK)4/6 inhibitors effectively antagonized AR(F876L) function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a "withdrawal" response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.

Significance: We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this fi nding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-13-0142DOI Listing
September 2013

Reciprocal regulation of protein kinase and pyruvate kinase activities of pyruvate kinase M2 by growth signals.

J Biol Chem 2013 May 10;288(22):15971-9. Epub 2013 Apr 10.

Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.

Pyruvate kinase isoform M2 (PKM2) is an enzyme-catalyzing conversion of phosphoenolpyruvate to pyruvate in the glycolysis pathway. It was demonstrated that PKM2 interacts with tyrosine phosphopeptide, and the interaction with the tyrosine phosphopeptide affects the pyruvate kinase activity of PKM2. Our experiments suggest that PKM2 is also an active protein kinase (Gao, X., Wang, H., Yang, J. J., Liu, X., and Liu, Z. R. (2012) Mol. Cell 45, 598-609). We report here that growth signals reciprocally regulate the pyruvate kinase and protein kinase activities of PKM2 by different mechanisms. On the one hand, growth signals induce protein tyrosine phosphorylations. The tyrosine-phosphorylated protein(s) regulates the conversion of pyruvate kinase and protein kinase of PKM2 by directly interacting with PKM2. Binding of the tyrosyl-phosphorylated proteins at the fructose 1,6-bisphosphate-binding site converts the tetrameric PKM2 to a dimer. On the other hand, growth stimulations also lead to PKM2 phosphorylation, which consequently regulates the conversion of protein kinase and pyruvate kinase activities. Growth factor stimulations significantly increase the dimer/tetramer PKM2 ratio in cells and consequently activate the protein kinase activity of PKM2. Our study suggests that the conversion between the pyruvate kinase and protein kinase activities of PKM2 may be an important mechanism mediating the effects of growth signals in promoting cell proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M112.448753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668752PMC
May 2013

Interaction between p68 RNA helicase and Ca2+-calmodulin promotes cell migration and metastasis.

Nat Commun 2013 ;4:1354

Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.

p68 RNA helicase is a prototypical RNA helicase. Here we present evidence to show that, by interacting with Ca-calmodulin, p68 has a role in cancer metastasis and cell migration. A peptide fragment that spans the IQ motif of p68 strongly inhibits cancer metastasis in two different animal models. The peptide interrupts p68 and Ca-calmodulin interaction and inhibits cell migration. Our results demonstrate that the p68-Ca-calmodulin interaction is essential for the formation of lamellipodia and filopodia in migrating cells. p68 interacts with microtubules in the presence of Ca-calmodulin. Our experiments show that interaction with microtubules stimulates p68 ATPase activity. Further, microtubule gliding assays demonstrate that p68, in the presence of Ca-calmodulin, can function as a microtubule motor. This motor activity may allow p68 to transport Ca-calmodulin to the leading edge of migrating cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms2345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552336PMC
June 2013

Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention.

Cancer Discov 2013 Jan 20;3(1):44-51. Epub 2012 Dec 20.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Unlabelled: Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors have yielded encouraging yet ultimately confounding results. Using a preclinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, in which surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the phosphoinositide 3-kinase (PI3K) signaling pathway via either genetic ablation of genes encoding PI3K components or pharmacologic inhibition of the PI3K pathway reversed the PTEN loss-induced HG-PIN phenotype. Finally, concurrent inhibition of the PI3K and mitogen-activated protein kinase (MAPK) pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of antiandrogen chemoprevention in certain genetic contexts (such as PTEN loss) while showing the promise of targeted therapy in the clinical management of this complex and prevalent disease.

Significance: Chemoprevention with antiandrogen therapies is attractive for prostate cancer, given its prevalence and established hormonally mediated pathogenesis. However, because PTEN loss has been found in 9% to 45% of HG-PIN in the clinic, the current findings suggest that patients with PTEN-deficient prostate tumors might be better treated with PI3K-targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-12-0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546223PMC
January 2013

Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.

Mol Cell 2012 Mar 2;45(5):598-609. Epub 2012 Feb 2.

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression of a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2012.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299833PMC
March 2012

P68 RNA helicase is a nucleocytoplasmic shuttling protein.

Cell Res 2009 Dec 29;19(12):1388-400. Epub 2009 Sep 29.

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

P68 RNA helicase is a prototypical DEAD box RNA helicase. The protein plays a very important role in early organ development and maturation. Consistent with the function of the protein in transcriptional regulation and pre-mRNA splicing, p68 was found to predominately localize in the cell nucleus. However, recent experiments demonstrate a transient cytoplasmic localization of the protein. We report here that p68 shuttles between the nucleus and the cytoplasm. The nucleocytoplasmic shuttling of p68 is mediated by two nuclear localization signal and two nuclear exporting signal sequence elements. Our experiments reveal that p68 shuttles via a classical RanGTPase-dependent pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/cr.2009.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788662PMC
December 2009

The recombinant beta subunit of C-phycocyanin inhibits cell proliferation and induces apoptosis.

Cancer Lett 2007 Mar 5;247(1):150-8. Epub 2006 Jun 5.

Department of Biology, Georgia Cancer Center, Georgia State University, University Plaza, Atlanta, GA 30303, USA.

C-Phycocyanin (C-PC) from blue-green algae has been reported to have various pharmacological characteristics, including anti-inflammatory and anti-tumor activities. In this study, we expressed the beta-subunit of C-PC (ref to as C-PC/beta) in Escherichia coli. We found that the recombinant C-PC/beta has anti-cancer properties. Under the treatment of 5 microM of the recombinant C-PC/beta, four different cancer cell lines accrued high proliferation inhibition and apoptotic induction. Substantially, a lower response occurred in non-cancer cells. We investigated the mechanism by which C-PC/beta inhibits cancer cell proliferation and induces apoptosis. We found that the C-PC/beta interacts with membrane-associated beta-tubulin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Under the treatment of the C-PC/beta, depolymerization of microtubules and actin-filaments were observed. The cells underwent apoptosis with an increase in caspase-3, and caspase-8 activities. The cell cycle was arrested at the G0/G1 phase under the treatment of C-PC/beta. In addition, the nuclear level of GAPDH decreased significantly. Decrease in the nuclear level of GAPDH prevents the cell cycle from entering into the S phase. Inhibition of cancer cell proliferation and induction of apoptosis may potentate the C-PC/beta as a promising cancer prevention or therapy agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2006.04.002DOI Listing
March 2007