Expression of Serotonin Receptors in Human Hepatocellular Cancer

Soll, Christopher; Riener, Marc‐Oliver; Oberkofler, Christian E.; Hellerbrand, Claus; Wild, Peter J.; DeOliveira, Michelle L.; Clavien, Pierre‐Alain

doi:10.1158/1078-0432.ccr-11-1813

Cited by 64 publications

(61 citation statements)

References 36 publications

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“…In prostate cancer, these growth factors act on the adjacent (exocrine) tumor cells to enhance tumor growth, differentiation and angiogenesis, the events that lead to a poor prognosis [18], [70]. Recently, 5-HT 1B receptors were associated with an increased proliferation index, correlated with the size of the tumor in hepatocellular cancer patients [71], and were shown to play a potential role in colorectal cancer [69]. Since we showed here that the 5-HT 1B and 5-HT 1D receptors are highly over-expressed in PaCa cells, we tried to explore the etiological associations between its expression and PaCa progression.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

et al. 2014

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Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B– and 5-HT1D–mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

et al. 2014

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“…Likewise, our data showed that pimozide decreased IL6-mediated STAT3 phosphorylation and could reverse cancer stem-like cell phenotypes induced by IL-6 addition in HCC cells, further suggesting that pimozide may be a potential agent for treating HCC cells by inhibiting STAT3 signaling and suppressing cancer stem-like cell maintenance. Besides, since pimozide is a well-known antagonist of serotonin 5-hydroxytryptamine receptor 7 (5HT7), which was overexpressed in human hepatocellular cancer (Data not shown, [49]), whether 5HT7 expression is associated with STAT3 activation in HCC cells is required to investigated in future.…”

Section: Discussionmentioning

confidence: 99%

The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma

et al. 2015

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Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti-cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3-dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC.

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“…26) Liang et al showed that serotonin was involved in tumorigenesis and induced a pro-proliferative effect in HCC cells via upregulation of expression of FOXO3a (a member of class O of the forkhead box family of transcription factors). 27) On the other hand, some reports indicated that serotonin reuptake transporter did not exist on liver tissue.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells

Kuwahara

Yamada

Egashira

et al. 2015

Biological & Pharmaceutical Bulletin

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The anti-tumor effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) on several types of cancer cells have been reported. However, comparison of the anti-tumor effects of these drugs on human hepatocellular carcinoma (HepG2) cells has not been studied. We compared the anti-tumor effects of four SSRIs and two SNRIs on HepG2 cells. SSRIs and duloxetine dose-dependently decreased cell viability. Milnacipran had no effect on cell viability. The half-maximal inhibitory concentration was lower in the order of: sertraline, paroxetine, duloxetine, fluvoxamine, escitalopram, and milnacipran. Exposure to sertraline (2 µM) significantly increased caspase-3/7 activity. These results suggest that, of the agents tested here, sertraline had the highest sensitivity to HepG2 cells, and activation of the caspase pathway is involved in the anti-tumor effects of sertraline in HepG2 cells.Key words selective serotonin reuptake inhibitor; anti-tumor effect; sertraline; serotonin and norepinephrine reuptake inhibitor; human hepatocellular carcinoma cell Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancerbased death.

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Expression of Serotonin Receptors in Human Hepatocellular Cancer

Cited by 64 publications

References 36 publications

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma

Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells

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