Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells

Guo, Qie; Sui, Zhongguo; Xu, Wen; Quan, Xianghua; Sun, Jialin; Xiao, Li; Ji, Hongyan; Jing, Fanbo

doi:10.18632/oncotarget.20194

Cited by 26 publications

(30 citation statements)

References 44 publications

(50 reference statements)

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“…However, the overall prognosis of patients with HCC is poor, and only a minority of HCC patients are eligible for surgical resection due to late stage diagnosis [4]. One of the greatest obstacles in HCC treatment is the occurrence of multi-drug resistance in response to chemotherapeutic drugs, such as 5-FU [5] and sorafenib [6,7]. Hence, the discovery of new potential therapeutic targets and treatment strategies has been a research hotspot for HCC.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway

et al. 2018

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Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid isolated from the medicinal plant S. involucrata, which exhibits anti-neoplastic activity against several types of cancer. However, the mechanism underlying its anti-cancer activity against hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we investigated whether and how hispidulin-induced apoptosis of human HCC cells in vitro and in vivo. We showed that hispidulin (10, 20 μmol/L) dose-dependently inhibited cell growth and promoted apoptosis through mitochondrial apoptosis pathway in human HCC SMMC7721 cells and Huh7 cells. More importantly, we revealed that its pro-apoptotic effects depended on endoplasmic reticulum stress (ERS) and unfolded protein response (UPR), as pretreatment with salubrinal, a selective ERS inhibitor, or shRNA targeting a UPR protein CHOP effectively abrogated hispidulin-induced cell apoptosis. Furthermore, we showed that hispidulin-induced apoptosis was mediated by activation of AMPK/mTOR signaling pathway as pretreatment with Compound C, an AMPK inhibitor, or AMPK-targeting siRNA reversed the pro-apoptotic effect of hispidulin. In HCC xenograft nude mice, administration of hispidulin (25, 50 mg kg d, ip, for 27 days) dose-dependently suppressed the tumor growth, accompanied by inducing ERS and apoptosis in tumor tissue. Taken together, our results demonstrate that hispidulin induces ERS-mediated apoptosis in HCC cells via activating the AMPK/mTOR pathway. This study provides new insights into the anti-tumor activity of hispidulin in HCC.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway

et al. 2018

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“…The same authors linked TGF-β-induced EMT to CD13 upregulation, promoting CSC survival by abrogating ROS production [183]. Several experimental approaches have been designed to target CD13 in HCC, most of them showing promising efficacy, especially in combination with cytotoxic agents [184][185][186][187][188][189]. The above-mentioned ubenimex is a protease inhibitor blocking CD13 activity and has been evaluated in other diseases; i.e., squamous cell lung carcinoma, lymphedema and pulmonary hypertension.…”

Section: Mechanisms Of Resistance To Therapy Of Cscsmentioning

confidence: 99%

The Cancer Stem Cell in Hepatocellular Carcinoma

Schulte

López-Gil

Sáinz

et al. 2020

Cancers

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The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

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“…A further potential therapeutic strategy is development of surface marker inhibitors, such as Ubenimex, which suppress CD13 and are widely used as an immunoenhancer for treating solid tumors and hematological neoplasms. Ubenimex is reported to reverse multidrug resistance (MDR) of HCC by suppressing Pim3, BCL-2, and BCL-XL expression, decreasing Bad phosphorylation and further enhancing tumor cell apoptosis [ 173 ].…”

Section: Interactions Of Lcscs Influencing Hcc and Therapeutic Strmentioning

confidence: 99%

Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies

Liu

Yeh

Lin

2020

Cells

189

134

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Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence self-renewal, differentiation, and tumorigenesis. A number of surface markers for liver cancer stem cell (LCSC) subpopulations (EpCAM, CD133, CD44, CD13, CD90, OV-6, CD47, and side populations) in HCC have been identified. LCSCs play critical roles in regulating HCC stemness, self-renewal, tumorigenicity, metastasis, recurrence, and therapeutic resistance via genetic mutations, epigenetic disruption, signaling pathway dysregulation, or alterations microenvironment. Accumulating studies have shown that biomarkers for LCSCs contribute to diagnosis and prognosis prediction of HCC, supporting their utility in clinical management and development of therapeutic strategies. Preclinical and clinical analyses of therapeutic approaches for HCC using small molecule inhibitors, oncolytic measles viruses, and anti-surface marker antibodies have demonstrated selective, efficient, and safe targeting of LCSC populations. The current review focuses on recent reports on the influence of LCSCs on HCC stemness, tumorigenesis, and multiple drug resistance (MDR), along with LCSC-targeted therapeutic strategies for HCC.

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Ubenimex suppresses Pim-3 kinase expression by targeting CD13 to reverse MDR in HCC cells

Cited by 26 publications

References 44 publications

RETRACTED ARTICLE: Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway

RETRACTED ARTICLE: Hispidulin induces ER stress-mediated apoptosis in human hepatocellular carcinoma cells in vitro and in vivo by activating AMPK signaling pathway

The Cancer Stem Cell in Hepatocellular Carcinoma

Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies

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