Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod

Choudhari, Sweeta R.; Khan, Muhammad A.; Harris, Genesis; Picker, Donald; Jacob, Gary S.; Block, Timothy; Shailubhai, Kunwar

doi:10.1158/1535-7163.mct-06-0561

Cited by 90Cytokine Signaling Pathways and InteractionsHepatocellular Carcinoma Treatment and PrognosisHepatitis B Virus Studies

Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod

Choudhari, Sweeta R., Khan, Muhammad A., Harris, Genesis, Picker, Donald, Jacob, Gary S., Block, Timothy, Shailubhai, Kunwar·2007·Molecular Cancer Therapeutics

DOI 10.1158/1535-7163.mct-06-0561

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Abstract

Atiprimod is a novel anticancer and antiangiogenic drug candidate which is currently being evaluated in patients with liver carcinoid and multiple myeloma. In this study, we report that atiprimod selectively inhibited proliferation and induced apoptosis in HCC cells that expressed either hepatitis B virus (HBV) or hepatitis C virus, through deactivation of protein kinase B (Akt) and signal transducers and activators of transcription 3 (STAT3) signaling. In HepG2 AD38 cells, which express HBV genome under the control of a tetracycline-off promoter, both Akt and STAT3 were constitutively activated in response to HBV expression. However, this constitutive activation was not sensitive to lamivudine, a drug that inhibits HBV replication without affecting its gene expression, suggesting that HBV replication per se might not be responsible for the activation. Interestingly, the electrophoretic mobility of p-STAT3 protein bands on immunoblot was slower when AD38 cells were cultured in the absence of tetracycline, suggesting a differential phosphorylation in response to HBV expression. In HCC cells, interleukin 6 stimulates the phosphorylation of STAT3 both at serine 727 and at tyrosine 705 positions. The interleukin 6-stimulated activation of STAT3 and Akt was inhibited not only by atiprimod but also by LY294002, a phosphoinositide-3-kinase-specific inhibitor, and by NS398, a cyclooxygenase-2-selective inhibitor. The combination of these compounds did not produce any additive effect,…

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Hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3.
“Both hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3 (328–330), while HTLV-I, Epstein–Barr virus and papilloma virus activate STAT3 and NF-κB (311, 331, 332).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [329]

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Avalle, L., Regis, G., & Poli, V. (2012) · Springer eBooks · doi:10.1007/978-3-7091-0891-8_17 · Cited by 6 · see citing works
G-749 Promotes Receptor Tyrosine Kinase TYRO3 Degradation and Induces Apoptosis in Both Colon Cancer Cell Lines and Xenograft Mouse Models
Kim, H. D., Park, E. J., Choi, E. K., Song, S. Y., Hoe, K., & Kim, D.-U. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.730241 · Cited by 7 · see citing works
Corilagin induces laryngeal cancer antiproliferation and inhibits growth factor and cytokine signaling pathways in vitro and in vivo
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Differential association of STAT3 and HK‐II expression in hepatitis B virus‐ and hepatitis C virus‐related hepatocellular carcinoma
Li, M., Wang, W.-H., Jin, R., Zhang, T., Li, N., Han, Q., Wei, P., & Liu, Z.-W. (2016) · Journal of Medical Virology · doi:10.1002/jmv.24498 · Cited by 6 · see citing works
“For instance, HBV genomeexpressing HepG2 AD38 cells was shown to have constitutively activated STAT3 in response to HBV expression [Choudhari et al., 2007].”
Background
Combination of atiprimod and the proteasome inhibitor bortezomib induces apoptosis of mantle cell lymphoma in vitro and in vivo.
Sun, L., Zhang, L., Qian, J., Yang, J., Yi, Q., Dong, W., & Wang, M. L. (2012) · Leukemia research : a Forum for Studies on Leukemia and Normal Hemopoiesis · doi:10.1016/j.leukres.2011.09.014 · Cited by 6 · see citing works
Aplasia Ras homologue member I overexpression induces apoptosis through inhibition of survival pathways in human hepatocellular carcinoma cells in culture and in xenograft
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“Targeting signalling pathways mediated by either Akt or NF-kB has been documented to inhibit proliferation and promote apoptosis in HCC cells (Qiao et al., 2006; Choudhari et al., 2007).”
Background
Many Ways to Communicate—Crosstalk between the HBV-Infected Cell and Its Environment
Walter, A. J., van de Klundert, M. V., & Jung, S. (2022) · Pathogens · doi:10.3390/pathogens12010029 · Cited by 5 · see citing works
“Besides regulating HBV RNA transcription, it has been observed that HBx expression can cause many, poorly understood effects on cells, such as the activation of cellular signalling pathways, disruption of the cell cycle, cell-cell interaction, and more.”
BackgroundInfluential
Treatment of streptozotocin-induced diabetic rats with Castanea sativa and Lactarius deterrimus extracts decreases liver damage by initiating activation of the Akt prosurvival kinase
Mihailović, M., Uskoković, A., Arambasic-Jovanovic, J., Grdović, N., Dinić, S., Poznanović, G., Franić, A., Djordjević, M., & Vidaković, M. (2020) · Archives of Biological Sciences · doi:10.2298/abs200410017m · Cited by 5
“Members of this family have also been implicated in liver regeneration where they regulate the process of hepatocyte proliferation and differentiation [29].”
Background
Role of IL‐6 activated STAT3 and TNF expression in obesity‐associated hepatocellular carcinoma
Beyazıt, Y., Kekilli, M., Kurt, M., Sayılır, A., Taş, A., & Onal, I. (2010) · Alimentary Pharmacology and Therapeutics · doi:10.1111/j.1365-2036.2010.04332.x · Cited by 5
Milciclib and sorafenib synergistically downregulate c-Myc to suppress tumor growth in an orthotopic murine model of human hepatocellular carcinoma
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“Cell proliferation assay: Cell proliferation assay was performed using WST-1 reagent (Sigma Aldrich, St Louis, MO) as described [23].”
MethodSelf-citation
A review of computational approaches for analysis of hepatitis C virus-mediated liver diseases.
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Patients vote with their feet for ‘On demand’ rabeprazole in the maintenance treatment phase of reflux oesophagitis
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Exploiting Nanostructured Lipid Carriers for Lamivudine Repurposing in Oncology Through Modulation of Key Molecular Pathways
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Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples
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A Triazaspirane Derivative Inhibits Migration and Invasion in PC3 Prostate Cancer Cells
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“Conversely, Choudhari et al. [42] noted a decrease in phosphorylated AKT (pS473-AKT) at concentrations of atiprimod ranging from 0.5 to 5 µM in other signaling pathways that determine tumor development, such as JAK-STAT3 and PI3K/Akt [7,11,42].”
BackgroundInfluential
Possible Involvement of Signal Transducer and Activator of Transcription-3 (STAT3) Signaling Pathway in the Initiation and Progression of Hepatocellular Carcinoma
Subramaniam, A., Shanmugam, M. K., Perumal, E., Li, F., Nachiyappan, A., Kumar, A., Tan, B., & Sethi, G. (2014) · Springer eBooks · doi:10.1007/978-81-322-1533-2_6 · Cited by 2 · see citing works
Overview of Hepatitis Viruses and Cancer
Block, T., Chang, J.-H., & Guo, J.-T. (2012) · doi:10.1007/978-1-4614-0016-5_21 · Cited by 1
Self-citation
表皮角化細胞のStat3 シグナル(後編)
Sano, S. (2010) · doi:10.2336/nishinihonhifu.72.229

Authors: Choudhari, S. R., Khan, M. A., Harris, G., Picker, D., Jacob, G. S., Block, T., & Shailubhai, K.
Affiliations: Baruch S. Blumberg Institute (US)
1Callisto Pharmaceuticals, Inc., New York, New York and
ORCID: Block, Timothy
Venue: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research (AACR)
Published: 2007-01-01
Volume: 6
Issue: 1
Pages: 112-121
ISSN: 1535-7163 (ISSN-L)
1538-8514
DOI: 10.1158/1535-7163.mct-06-0561
OpenAlex: W2137547634
Cited by: 90
References: 0
Citations by year: 2025: 1 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 10 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 3 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 6
FWCI: 3.87
Type: journal article
Language: en
Open access: closed
Locations: Molecular Cancer Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
Keywords: hepatocellular carcinoma, Akt signaling, STAT3 signaling, apoptosis, cell proliferation inhibition, hepatitis B virus, hepatitis C virus, interleukin-6, STAT3 phosphorylation, phosphatidylinositol 3-kinase, cyclooxygenase-2, LY294002, NS-398, lamivudine, anticancer drug sensitivity
MeSH terms: Antineoplastic Agents, Enzyme Activation, Hepatitis B virus, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Models, Biological, Phosphorylation, Spiro Compounds, Virus Replication, Signal Transduction, Interleukin-6, Gene Expression Regulation, Viral, Hepacivirus, Apoptosis, Phosphatidylinositol 3-Kinases, Cell Proliferation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Cyclooxygenase 2

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Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod

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