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1.
Biomaterials ; 302: 122296, 2023 11.
Article in English | MEDLINE | ID: mdl-37696204

ABSTRACT

Mesenchymal stem cells (MSCs) are potential candidates in cell-based therapy for cartilage repair and regeneration. However, during chondrogenic differentiation, MSCs undergo undesirable hypertrophic maturation. This poses a risk of ossification in the neo-tissue formed that eventually impedes the clinical use of MSCs for cartilage repair. TGF-ß is a potent growth factor used for chondrogenic differentiation of MSCs, however, its role in hypertrophy remains ambiguous. In the present work, we decipher that TGF-ß activates Wnt/ß-catenin signaling through SMAD3 and increases the propensity of Infrapatellar fat pad derived MSCs (IFP-MSCs) towards hypertrophy. Notably, inhibiting TGF-ß induced Wnt/ß-catenin signaling suppresses hypertrophic progression and enhances chondrogenic ability of IFP-MSCs in plasma hydrogels. Additionally, we demonstrate that activating Wnt signaling during expansion phase, promotes proliferation and reduces senescence, while improving stemness of IFP-MSCs. Thus, conversely modulating Wnt signaling in vitro during expansion and differentiation phases generates hyaline-like cartilage with minimal hypertrophy. Importantly, pre-treatment of IFP-MSCs encapsulated in plasma hydrogel with Wnt modulators followed by subcutaneous implantation in nude mice resulted in formation of a cartilage tissue with negligible calcification. Overall, this study provides technological advancement on targeting Wnt/ß-catenin pathway in a 3D scaffold, while maintaining the standard chondro-induction protocol to overcome the challenges associated with the clinical use of MSCs to engineer hyaline cartilage.


Subject(s)
Hyaline Cartilage , Mesenchymal Stem Cells , Animals , Mice , Adipose Tissue , beta Catenin/metabolism , Cell Differentiation , Cells, Cultured , Chondrogenesis , Hydrogels , Hypertrophy/metabolism , Mice, Nude , Tissue Engineering/methods , Transforming Growth Factor beta/metabolism , Wnt Signaling Pathway
2.
Cell Death Dis ; 13(12): 1045, 2022 12 15.
Article in English | MEDLINE | ID: mdl-36522339

ABSTRACT

Owing to its ability to induce cellular senescence, inhibit PCNA, and arrest cell division cycle by negatively regulating CDKs as well as being a primary target of p53, p21 is traditionally considered a tumor suppressor. Nonetheless, several reports in recent years demonstrated its pro-oncogenic activities such as apoptosis inhibition by cytosolic p21, stimulation of cell motility, and promoting assembly of cyclin D-CDK4/6 complex. These opposing effects of p21 on cell proliferation, supported by the observations of its inconsistent expression in human cancers, led to the emergence of the concept of "antagonistic duality" of p21 in cancer progression. Here we demonstrate that p21 negatively regulates basal autophagy at physiological concentration. Akt activation, upon p21 attenuation, driven ROS accumulation appears to be the major underlying mechanism in p21-mediated modulation of autophagy. We also find p21, as a physiological inhibitor of autophagy, to have oncogenic activity during early events of tumor development while its inhibition favors survival and growth of cancer cells in the established tumor. Our data, thereby, reveal the potential role of autophagy in antagonistic functional duality of p21 in cancer.


Subject(s)
Proto-Oncogene Proteins c-akt , Tumor Suppressor Protein p53 , Humans , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Autophagy
3.
Mol Pharm ; 19(3): 831-842, 2022 03 07.
Article in English | MEDLINE | ID: mdl-35191706

ABSTRACT

To address the need for localized chemotherapy against unresectable solid tumors, an injectable in situ depot-forming lipidic lyotropic liquid crystal system (L3CS) is explored that can provide spatiotemporal control over drug delivery. Although liquid crystals have been studied extensively before but their application as an injectable intratumoral depot system for locoregional chemotherapy has not been explored yet. The developed L3CS in the present study is a low-viscosity injectable fluid having a lamellar phase, which transforms into a hexagonal mesophase depot system on subcutaneous or intratumoral injection. The transformed depot system can be preprogrammed to provide tailored drug release intratumorally, over a period of one week to one month. To establish the efficacy of the developed L3CS, doxorubicin is used as a model drug. The drug release mechanism is studied in detail both in vitro and in vivo, and the efficacy of the developed system is investigated in the murine 4T1 tumor model. The direct intratumoral injection of the L3CS provided localized delivery of doxorubicin inside the tumor and restricted its access within the tumor only for a sustained period of time. This led to an over 10-fold reduction in tumor burden, reduced cardiotoxicity, and a significant increase in the median survival rate, compared to the control group. The developed L3CS thus provides an efficient strategy for localized chemotherapy against unresectable solid tumors with a great degree of spatial and temporal control over drug delivery.


Subject(s)
Liquid Crystals , Animals , Cardiotoxicity , Doxorubicin , Drug Liberation , Lipids , Mice
4.
Cell Death Dis ; 12(5): 464, 2021 05 08.
Article in English | MEDLINE | ID: mdl-33966046

ABSTRACT

Chemokine receptor CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, blockade of CXCL12-CXCR4 signaling axis by inhibitors like Nox-A12, FDA approved CXCR4 inhibitor drug AMD3100 have shown limited clinical success in cancer treatment. Therefore, exclusive contribution of CXCR4-CXCL12 signaling in pro-tumorigenic function is questionable. In our pursuit to understand the impact of chemokine signaling in carcinogenesis, we reveal that instead of CXCR4-CXCL12 signaling, presence of CXCR4 intracellular protein augments paclitaxel resistance and pro-tumorigenic functions. In search of pro-apoptotic mechanisms for CXCR4 mediated drug resistance; we discover that DR5 is a new selective target of CXCR4 in breast and colon cancer. Further, we detect that CXCR4 directs the differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 in course of its transcriptional repression. Remarkably, inhibiting CXCR4-ligand-mediated signals completely fails to block the above phenotype. Overexpression of different mutant versions of CXCR4 lacking signal transduction capabilities also result in marked downregulation of DR5 expression in colon cancer indeed confirms the reverse relationship between DR5 and intracellular CXCR4 protein expression. Irrespective of CXCR4 surface expression, by utilizing stable gain and loss of function approaches, we observe that intracellular CXCR4 protein selectively resists and sensitizes colon cancer cells against paclitaxel therapy in vitro and in vivo. Finally, performing TCGA data mining and using human breast cancer patient samples, we demonstrate that expression of CXCR4 and DR5 are inversely regulated. Together, our data suggest that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.


Subject(s)
Breast Neoplasms/genetics , Drug Resistance, Neoplasm/drug effects , Receptors, CXCR4/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Cell Line, Tumor , Female , Humans
5.
Nat Commun ; 11(1): 384, 2020 01 20.
Article in English | MEDLINE | ID: mdl-31959826

ABSTRACT

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neuroendocrine Tumors/genetics , Prostatic Neoplasms/genetics , Trypsin Inhibitor, Kazal Pancreatic/metabolism , Androgen Receptor Antagonists/therapeutic use , Animals , Casein Kinase I/antagonists & inhibitors , Casein Kinase I/metabolism , Cell Line, Tumor , Co-Repressor Proteins/metabolism , HEK293 Cells , Humans , Male , Mice , Nerve Tissue Proteins/metabolism , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Prostate/drug effects , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Receptors, Androgen/metabolism , SOXB1 Transcription Factors/metabolism , Transcription, Genetic/drug effects , Up-Regulation/drug effects , Xenograft Model Antitumor Assays
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