CD44 variant‐dependent redox status regulation in liver fluke‐associated cholangiocarcinoma: A target for cholangiocarcinoma treatment

Thanee, Malinee; Loilome, Watcharin; Techasen, Anchalee; Sugihara, Eiji; Okazaki, Shogo; Abe, Shinya; Ueda, Satomi; Masuko, Takashi; Namwat, Nisana; Khuntikeo, Narong; Titapun, Attapol; Pairojkul, Chawalit; Saya, Hideyuki; Yongvanit, Puangrat

doi:10.1111/cas.12967

Cited by 57 publications

(60 citation statements)

References 46 publications

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“…To test this, we examined the sub-G1 population by flow cytometry in MDA-MB-231 and HCT116 cells after treatment with vorinostat and/or SASP for 144 h. Vorinostat induced marked cell death in both cell lines when cotreated with SASP at 500 µM ( Figure 4A), which was close or below to IC50 values in MDA-MB-231 and HCT116 cells (Supplementary Figure S1B). inflammatory bowel disease and rheumatoid arthritis, has been considered to be repurposed as a promising antitumor drug [24][25][26][27][28][29][30][31][32].…”

Section: Sasp Increases Sensitivity To Vorinostat By Reducing Intracementioning

confidence: 99%

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

Miyamoto

Watanabe

Boku

et al. 2020

Cancers

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As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.

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Section: Sasp Increases Sensitivity To Vorinostat By Reducing Intracementioning

confidence: 99%

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

Miyamoto

Watanabe

Boku

et al. 2020

Cancers

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“…13 Sulfasalazine is an inhibitor of xCT-mediated cystine transporters 14 and exerts inhibitory effects against tumor growth, invasion, and metastasis in many types of cancers. 4,[15][16][17][18][19] Furthermore, previous studies reported that SSZ enhanced the effects of CDDP therapy. 20,21 However, limited information is currently available on the functional role of SSZ, which could modulate the CD44v9-xCT system in order to enhance CDDP-induced cytotoxicity and inhibit the metastatic potential of BC.…”

Section: Introductionmentioning

confidence: 97%

“…We focused on SSZ, an anti‐inflammatory drug approved for the treatment of inflammatory bowel disease and rheumatoid arthritis . Sulfasalazine is an inhibitor of xCT‐mediated cystine transporters and exerts inhibitory effects against tumor growth, invasion, and metastasis in many types of cancers . Furthermore, previous studies reported that SSZ enhanced the effects of CDDP therapy .…”

Section: Introductionmentioning

confidence: 99%

Sulfasalazine could modulate the CD44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer

et al. 2019

Self Cite

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The prognostic role of CD 44v9, a variant isoform of CD 44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer ( BC ) patients. Furthermore, limited information is available on the functional role of sulfasalazine ( SSZ ), which could modulate the CD 44v9‐ xCT system in order to enhance cisplatin ( CDDP )‐induced cytotoxicity and inhibit the metastatic potential of BC . CD 44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC ( MIBC ) patients who underwent radical cystectomy. CD 44v9 expression was independently associated with disease recurrence and cancer‐specific death in MIBC . Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD 44v9 and phospho‐p38 MAPK protein expression by SSZ with or without CDDP were assessed in MBT ‐2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT ‐2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT ‐2V cells by inhibiting CD 44v9 expression and upregulating phospho‐p38 MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT ‐2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD 44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC .

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“…However, even if investigation of PLC metabolism is still at its very beginning in comparison with other tumor systems, recent evidence has revealed the importance of the metabolic rearrangement in PLC CSCs. CD44+ CCA CSCs adapt their redox status regulation according to their needs and contribute to reactive oxygen species (ROS) defense promoting glutathione synthesis by way of xCT (a cysteine-glutamate transporter), resulting in evasion of cell death [142] . Moreover, CD133+ HCC CSCs are characterized by high glycolytic metabolism with concomitant overexpression of glycolytic genes and enhanced extracellular acidification rate, demonstrating that CD133+ cells are more glycolytic compared to CD133-cells.…”

Section: Metabolic Reprogrammingmentioning

confidence: 99%

Stemness features in liver cancer

Correnti¹,

Booijink²,

Maira³

et al. 2018

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Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemoresistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies.Primary liver cancer (PLC) is one of the most common cancers worldwide and the second leading cause of cancer-related mortality [1,2] . The major forms of PLC comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) [1,3-5] . HCC accounts for approximately 90% of all PLCs [1,3] , while CCA is the second most common form and accounts for about 5% of all PLCs [3][4][5] . HCC causes over 600,000 deaths worldwide annually, and its incidence and mortality are increasing at a fast rate [6-10] . On the other hand, CCA is characterized by a very poor prognosis, with a 5-years survival lower than 20%, and its incidence and worldwide mortality are also increasing [5,[11][12][13] . The high mortality rate of CCA may depend on its nonspecific or silent clinical features and the lack of specific markers that make it difficult to diagnose [14][15][16] .Many studies carried out in these last years have attempted to define which type of epithelial cell [hepatocytes, cholangiocytes, hepatic progenitor cells (HPCs) or all three] should be considered as the PLC cell of origin [17] . For a long time, HCC and CCA have been commonly accepted to derive from hepatocytes and cholangiocytes, respectively. Since mature hepatocytes and cholangiocytes have an enormous selfrenewal capacity and longevity, they meet the requirements to be targets for oncogenesis [17][18][19][20][21][22][23] . Detailed analyses of a wide range of PLC tumor types have reported that a rare form of combined HCC-CCA (cHCC-CCA) has intermediate characteristics between HCC and intrahepatic CCA (iCCA), suggesting that they could share the same stem/progenitor cell origin [18][19][20][21][22][23][24] . In this regard, since most PLCs arise on the background of chronic liver disease in the presence of an ex...

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CD44 variant‐dependent redox status regulation in liver fluke‐associated cholangiocarcinoma: A target for cholangiocarcinoma treatment

Cited by 57 publications

References 46 publications

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

Sulfasalazine could modulate the CD44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer

Stemness features in liver cancer

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