Publications by authors named "Pramod S Gowda"

5 Publications

  • Page 1 of 1

Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites.

Cancer Res 2020 03 7;80(5):1036-1048. Epub 2020 Jan 7.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.

Multiple myeloma is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that multiple myeloma cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OB) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote multiple myeloma dissemination to and progression in these areas. Hence, we developed a syngeneic mouse model of multiple myeloma in which Runx2 is specifically deleted in the immature OBs of C57BL6/KaLwRij mice (OB-Runx2 mice) to study the effect of OB-Runx2 deficiency on multiple myeloma progression in new bone sites. studies with this model demonstrated that OB-Runx2 deficiency attracts multiple myeloma cells and promotes multiple myeloma tumor growth in bone. Mechanistic studies further revealed that OB-Runx2 deficiency induces an immunosuppressive microenvironment in BM that is marked by an increase in the concentration and activation of myeloid-derived suppressor cells (MDSC) and the suppression and exhaustion of cytotoxic CD8 T cells. In contrast, MDSC depletion by either gemcitabine or 5-fluorouracil treatment in OB-Runx2 mice prevented these effects and inhibited multiple myeloma tumor growth in BM. These novel discoveries demonstrate that OB-Runx2 deficiency in new bone sites promotes multiple myeloma dissemination and progression by increasing metastatic cytokines and MDSCs in BM and inhibiting BM immunity. Importantly, MDSC depletion can block multiple myeloma progression promoted by OB-Runx2 deficiency. This study demonstrates that Runx2 deficiency in immature osteoblasts at distant bone sites attracts myeloma cells and allows myeloma progression in new bone sites via OB-secreted metastatic cytokines and MDSC-mediated suppression of bone marrow immunity.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056521PMC
March 2020

Runx2 Suppression by miR-342 and miR-363 Inhibits Multiple Myeloma Progression.

Mol Cancer Res 2018 07 28;16(7):1138-1148. Epub 2018 Mar 28.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.

In multiple myeloma, abnormal plasma cells accumulate and proliferate in the bone marrow. Recently, we observed that Runx2, a bone-specific transcription factor, is highly expressed in multiple myeloma cells and is a major driver of multiple myeloma progression in bone. The primary goal of the present study was to identify Runx2-targeting miRNAs that can reduce tumor growth. Expression analysis of a panel of miRNAs in multiple myeloma patient specimens, compared with healthy control specimens, revealed that metastatic multiple myeloma cells express low levels of miR-342 and miR-363 but high levels of Runx2. Reconstituting multiple myeloma cells (CAG) with miR-342 and miR-363 reduced the abundance of Runx2 and the expression of metastasis-promoting Runx2 target genes RANKL and DKK1, and suppressed Runx2 downstream signaling pathways Akt/β-catenin/survivin, which are required for multiple myeloma tumor progression. Intravenous injection of multiple myeloma cells (5TGM1), stably overexpressing miR-342 and miR-363 alone or together, into syngeneic C57Bl/KaLwRij mice resulted in a significant suppression of 5TGM1 cell growth, decreased osteoclasts and increased osteoblasts, and increased antitumor immunity in the bone marrow, compared with mice injected with 5TGM1 cells expressing a miR-Scramble control. In summary, these results demonstrate that enhanced expression of miR-342 and miR-363 in multiple myeloma cells inhibits Runx2 expression and multiple myeloma growth, decreases osteolysis, and enhances antitumor immunity. Thus, restoring the function of Runx2-targeting by miR-342 and miR-363 in multiple myeloma cells may afford a therapeutic benefit by preventing multiple myeloma progression. miR-342 and miR-363-mediated downregulation of Runx2 expression in multiple myeloma cells prevents multiple myeloma progression. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030427PMC
July 2018

Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone.

Am J Pathol 2016 11 17;186(11):3054-3063. Epub 2016 Sep 17.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Comprehensive Cancer Center and the Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address:

Multiple myeloma (MM) cells reside in the bone marrow microenvironment and form complicated interactions with nonneoplastic, resident stromal cells. We previously found that aggressive MM cells shift osteoblast progenitors toward adipogenesis. In addition, adipocytes are among the most common cell types in the adult skeleton; both mature adipocytes and preadipocytes serve as endocrine cells that secrete a number of soluble molecules into the microenvironment. Therefore, we used a combination of in vivo and in vitro methods to test the hypothesis that an increase in adipocyte lineage cells feeds back to promote MM progression. The results of this study revealed that bone marrow from patients with MM indeed contains increased preadipocytes and significantly larger mature adipocytes than normal bone marrow. We also found that preadipocytes and mature adipocytes secrete many molecules important for supporting MM cells in the bone marrow and directly recruit MM cells through both monocyte chemotactic protein-1 and stromal cell-derived factor-1α. Co-culture experiments found that preadipocytes activate Wnt signaling and decrease cleaved caspase-3, whereas mature adipocytes activate ERK signaling in MM cells. Furthermore, mature adipocyte conditioned medium promotes MM growth, whereas co-culture with preadipocytes results in enhanced MM cell chemotaxis in vitro and increased tumor growth in bone in vivo. Combined, these data reveal the importance of preadipocytes and mature adipocytes on MM progression and represent a unique target in the bone marrow microenvironment.
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http://dx.doi.org/10.1016/j.ajpath.2016.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222958PMC
November 2016

Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression.

Mol Cancer Res 2013 Nov 29;11(11):1448-61. Epub 2013 Aug 29.

Department of Cellular & Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7762, San Antonio, TX 78229-3900.

Unlabelled: Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC.

Implications: Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth.
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http://dx.doi.org/10.1158/1541-7786.MCR-13-0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834015PMC
November 2013

p53 binding prevents phosphatase-mediated inactivation of diphosphorylated c-Jun N-terminal kinase.

J Biol Chem 2012 May 30;287(21):17554-17567. Epub 2012 Mar 30.

Departments of Biochemistry and The University of Texas Health Science Center, San Antonio, Texas 78229; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229. Electronic address:

c-Jun N-terminal kinase (JNK) is a serine/threonine phosphotransferase whose sustained activation in response to genotoxic stress promotes apoptosis. In Drosophila, the normally rapid JNK-dependent apoptotic response to genotoxic stress is significantly delayed in Dmp53 (Drosophila p53) mutants. Likewise, the extent of JNK activity after UV irradiation is dependent on p53 in murine embryonic fibroblasts with loss of p53 resulting in diminished JNK activity. Together, these results suggest that p53 potentiates the JNK-dependent response to genotoxic stress; however, the mechanism whereby p53 stimulates JNK activity remains undefined. Here, we demonstrate that both Drosophila and human p53 can directly stimulate JNK activity independently of p53-dependent gene transcription. Furthermore, we demonstrate that both the Drosophila and human p53 orthologs form a physical complex with diphosphorylated JNK ((DP)JNK) both in vivo and in vitro, suggesting that the interaction is evolutionarily conserved. Focusing on human p53, we demonstrate that the interaction maps to the DNA binding domain (hp53(DBD)). Intriguingly, binding of p53(DBD) alone to (DP)JNK prevented its inactivation by MAPK phosphatase (MKP)-5; however, JNK was still able to phosphorylate c-Jun while in a complex with the p53(DBD). Apparent dissociation constants for the p53(DBD)·(DP)JNK (274 ± 14 nm) and MKP-5·(DP)JNK (55 ± 8 nm) complexes were established; however, binding of MKP-5 and p53 to JNK was not mutually exclusive. Together, these results suggest that stress-dependent increases in p53 levels potentiate JNK activation by preventing its rapid dephosphorylation by MKPs and that the simultaneous activation of p53 and JNK may constitute a "fail-safe" switch for the JNK-dependent apoptotic response.
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http://dx.doi.org/10.1074/jbc.M111.319277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366850PMC
May 2012