Papers by Ravshan Burikhanov
PubMed, Jun 1, 2000
Objective: Excess iodine and some iodine-containing compounds are known to affect various paramet... more Objective: Excess iodine and some iodine-containing compounds are known to affect various parameters of thyroid function. Lecithin-bound iodine (LBI) is a compound which induces involution of an enlarged thyroid. LBI was tested for its ability to affect thyroid ornithine decarboxylase (ODC) activity and apoptosis. Methods: LBI was given orally to propylthiouracil-pretreated rats and the changes in ODC activity and apoptosis were observed. The thyroid apoptosis was detected by DNA laddering and flow cytometry. Results: LBI suppressed the thyroid ODC activity within one hour after its administration and lowered slightly but significantly the thyroid putrescine levels at 3 h. The DNA cleavage ladder was evident at 3-6 h after LBI treatment. Propylthiouracil induced thyroid enlargement was reduced significantly at 3 days after chronic treatment with LBI. The thyroidal content of putrescine was also decreased after chronic treatment. These effects of LBI were essentially the same as those of excess iodide, while other iodinated compounds including amiodarone, iopanoic acid and erythrosine had no effect on the thyroid ODC activity. Conclusions: These results suggest that LBI may exert its anti-goitrous effects, consisting of the inhibition of ODC activity and apoptosis, in the form of inorganic iodide in vivo.
Neuroscience and Behavioral Physiology, Nov 1, 1994
Conclusions 1. The immobilization of rats for 2 min with repetition after 3 min induces a sign... more Conclusions 1. The immobilization of rats for 2 min with repetition after 3 min induces a significant increase in the secretion of thyroid hormones. 2. This increase in secretion is abolished by the administration of the α-blocker prazosin 1 h before exposure. 3. The acute stress induced by repeated immobilization increases the activity of the thyroid conversion of T4.
Genes & Cancer, Nov 3, 2018
Chloroquine and hydroxychloroquine (HCQ) are robust inducers of the tumor suppressor Par-4 secret... more Chloroquine and hydroxychloroquine (HCQ) are robust inducers of the tumor suppressor Par-4 secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells and inhibits metastasis in mice. We report the clinical results with pharmacodynamic analyses of our Phase I trial using neoadjuvant administration of HCQ in patients with surgically removable early stage solid tumors. This was a single-institution trial of oral HCQ (200 or 400 mg twice daily) given for 14 days prior to planned surgery. Dose escalation was based on isotonic regression to model safety and biological effect based on plasma Par-4 analysis. Eight of the nine patients treated with HCQ showed elevation in plasma Par-4 levels over basal levels. No toxicities were observed with these dose regimens. The resected tumors from the eight HCQ-treated patients with elevated plasma Par-4 levels, but not the resected tumor from the patient who failed to induce plasma Par-4 levels, exhibited TUNELpositivity indicative of apoptosis. Resected tumors from all nine HCQ-treated patients showed p62/sequestosome-1 induction indicative of autophagy-inhibition by HCQ. Our findings indicate that both dose levels of HCQ were well-tolerated and that Par-4 secretion but not induction of the autophagy-inhibition marker p62 correlated with apoptosis induction in patients' tumors.
Problemy e̊ndokrinologii, Oct 14, 1993
Analysis of blood flowing from the rat thyroid has shown that an acute immobilization stress enha... more Analysis of blood flowing from the rat thyroid has shown that an acute immobilization stress enhanced thyroid hormone secretion with an increase of the T3/T4-100 index. The most marked response to stress was observed after repeated 2 min immobilization with a 3 min interval: Such increase of secretion was arrested by injection of prasosin, an -adrenoblocker. Propylthiouracil injected an hour before the experiment reduced T4 thyroid conversion index. These results permit a conclusion that short-term repeated immobilization enhanced thyroid hormone secretion via -adrenergic system stimulation, this being paralleled by increased production of hormonally more active T3.
Deletion or mutation of the androgen receptor (AR) renders prostate tumors refractory to apoptosi... more Deletion or mutation of the androgen receptor (AR) renders prostate tumors refractory to apoptosis by androgen ablation, the mainstay of prostate cancer therapy. To identify novel therapeutics that can induce apoptosis regardless of the AR status of prostate cancer cells, we screened dietary herbal compounds using a reporter assay for the prostate apoptosis response-4 (Par-4) gene, which induces p53- and PTEN-independent and cancer-selective apoptosis. One of the compounds, withaferin A (WA), a major constituent of the dietary compound Withania somnifera, induced Par-4-dependent apoptosis in androgen-refractory prostate cancer cells and regression of PC-3 xenografts in nude mice. Interestingly, restoration of wild-type AR in PC-3 (AR negative) cells abrogated both Par-4 induction and apoptosis by WA. Individually, WA and anti-androgens induced neither Par-4 nor apoptosis in androgen-responsive prostate cancer cells, yet in combination, WA and anti-androgen synergistically induced Par-4 and apoptosis in androgen-responsive prostate cancer cells. Thus, when judiciously combined with anti-androgens, WA inhibits survival of both androgen-responsive and androgen-refractory prostate cancer cells by a Par-4-dependent mechanism. As Par-4 up-regulation induces apoptosis in most tumor cells, our findings can be extended to high-throughput screens to identify synergistic combinations for both therapy-sensitive and therapy-resistant cancers. [Cancer Res 2007;67(1):246–53]
WA up-regulates Par-4 RNA levels To ascertain whether Par-4 is up-regulated by WA at the RNA leve... more WA up-regulates Par-4 RNA levels To ascertain whether Par-4 is up-regulated by WA at the RNA level, PC-3 cells were treated with WA (4 µM), and total RNA from the cells was quantified by RT-PCR and ethidium bromide gel
Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in can... more Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-κB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance. [Cancer Res 2007;67(19):9276–85]
Nature Chemical Biology, Sep 14, 2014
The tumor suppressor protein Par-4, which is secreted by normal cells, selectively induces apopto... more The tumor suppressor protein Par-4, which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds to Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Cancer Research, Nov 1, 2007
Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by... more Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by which Ras induces cellular transformation is, however, not fully elucidated. We present here evidence that oncogenic Ras suppresses the expression of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN), and this action of oncogenic Ras is mediated by the Raf-mitogenactivated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway via up-regulation of c-Jun. Jun +/+ cells undergo cellular transformation by oncogenic Ras, and restoration of wild-type PTEN, but not a phosphatedefective mutant of PTEN, induces apoptosis in these cells. Conversely, in Jun À/À cells, oncogenic Ras neither suppresses PTEN nor causes transformation, but rather it induces PTENdependent apoptosis. An apoptotic response to oncogenic Ras in Jun À/À cells can be prevented by suppressing PTEN expression. These findings imply that oncogenic Ras suppresses the apoptotic gene PTEN via the Raf-MEK-ERK-c-Jun pathway to induce antiapoptosis and cellular transformation. Together, our findings identify a novel molecular interface between the oncogenic and tumor suppressor pathways that regulates cellular transformation and survival.
Molecular and Cellular Biology, Aug 1, 2003
Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certai... more Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-B transcriptional activity. However, the intracellular localization or functional domains of Par-4 involved in apoptosis remained unknown. In the present study, structure-function analysis indicated that inhibition of NF-B activity and apoptosis is dependent on Par-4 translocation to the nucleus via a bipartite nuclear localization sequence, NLS2. Cancer cells that were resistant to Par-4-induced apoptosis retained Par-4 in the cytoplasm. Interestingly, a 59-amino-acid core that included NLS2 but not the C-terminal leucine zipper domain was necessary and sufficient to induce Fas pathway activation, inhibition of NF-B activity, and apoptosis. Most important, this core domain had an expanded target range for induction of apoptosis, extending to previously resistant cancer cells but not to normal cells. These findings have identified a unique death-inducing domain selective for apoptosis induction in cancer cells (SAC domain) which holds promise for identifying key differences between cancer and normal cells and for molecular therapy of cancer.
Cancer Research, Jan 15, 2013
Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its... more Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-kB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-kB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-kB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-kB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. Cancer Res; 73(2); 1011-9. Ó2012 AACR.
Molecular Cell, Oct 1, 2005
Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homol... more Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.
PubMed, 2023
Lung cancer is the leading cause of cancer-related deaths. Lung cancer cells develop resistance t... more Lung cancer is the leading cause of cancer-related deaths. Lung cancer cells develop resistance to apoptosis by suppressing the secretion of the tumor suppressor Par-4 protein (also known as PAWR) and/or down-modulating the Par-4 receptor GRP78 on the cell surface (csGRP78). We sought to identify FDA-approved drugs that elevate csGRP78 on the surface of lung cancer cells and induce Par-4 secretion from the cancer cells and/or normal cells in order to inhibit cancer growth in an autocrine or paracrine manner. In an unbiased screen, we identified crizotinib (CZT), an inhibitor of activated ALK/MET/ROS1 receptor tyrosine kinase, as an inducer of csGRP78 expression in ALK-negative, KRAS or EGFR mutant lung cancer cells. Elevation of csGRP78 in the lung cancer cells was dependent on activation of the non-receptor tyrosine kinase SRC by CZT. Inhibition of SRC activation in the cancer cells prevented csGRP78 translocation but promoted Par-4 secretion by CZT, implying that activated SRC prevented Par-4 secretion. In normal cells, CZT did not activate SRC and csGRP78 elevation but induced Par-4 secretion. Consequently, CZT induced Par-4 secretion from normal cells and elevated csGRP78 in the ALK-negative tumor cells to cause paracrine apoptosis in cancer cell cultures and growth inhibition of tumor xenografts in mice. Thus, CZT induces differential activation of SRC in normal and cancer cells to trigger the pro-apoptotic Par-4-GRP78 axis. As csGRP78 is a targetable receptor, CZT can be repurposed to elevate csGRP78 for inhibition of ALK-negative lung tumors.
Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resist... more Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA segment, competitively bound to Fbxo45 and rescued Par-4–mediated induction of cancer cell–specific apoptosis. Collectively, our findings identify a molecular decoy naturally generated during apoptosis that inhibits a ubiquitin ligase to overcome therapy resistance in tumors. Cancer Res; 77(15); 4039–50. ©2017 AACR.
In the present study, ionizing radiation (IR)–induced bystander effects were investigated in two ... more In the present study, ionizing radiation (IR)–induced bystander effects were investigated in two lung cancer cell lines. A549 cells were found to be more resistant to radiation-conditioned medium (RCM) obtained from A549 cells when compared with the H460 exposed to RCM procured from H460 cells. Significant release of tumor necrosis factor-α (TNF-α) was observed in A549 cells after IR/RCM exposure, and the survival was reversed with neutralizing antibody against TNF-α. In H460 cells, significant release of TNF-related apoptosis-inducing ligand (TRAIL), but not TNF-α, was observed in response to IR, RCM exposure, or RCM + 2Gy, and neutralizing antibody against TRAIL diminished clonogenic inhibition. Mechanistically, TNF-α present in RCM of A549 was found to mediate nuclear factor-κB (NF-κB) translocation to nucleus, whereas the soluble TRAIL present in RCM of H460 cells mobilized the nuclear translocation of PAR-4 (a proapoptotic protein). Analysis of IR-inducible early growth response-1 (EGR-1) function showed that EGR-1 was functional in A549 cells but not in H460 cells. A significant decrease in RCM-mediated apoptosis was observed in both A549 cells stably expressing small interfering RNA EGR-1 and EGR-1−/− mouse embryonic fibroblast cells. Thus, the high-dose IR-induced bystander responses in A549 may be dependent on the EGR-1 function and its target gene TNF-α. These findings show that the reduced bystander response in A549 cells is due to activation of NF-κB signaling by TNF-α, whereas enhanced response to IR-induced bystander signaling in H460 cells was due to release of TRAIL associated with nuclear translocation of PAR-4. [Cancer Res 2007;67(24):11811–20]
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Papers by Ravshan Burikhanov