The c-MET/PI3K Signaling Is Associated with Cancer Resistance to Doxorubicin and Photodynamic Therapy by Elevating BCRP/ABCG2 Expression

Jung, Kyeong-Ah; Choi, Byungjoo; Kwak, Mi‐Kyoung

doi:10.1124/mol.114.096065

Cited by 54 publications

(34 citation statements)

References 58 publications

(72 reference statements)

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“…1a). Levels of BCRP and c-MET were also high in A2780DR, which confirms our previous observation 36 . Flow cytometry showed high ALDH1A1 levels in A2780DR due to an increase of ALDH1-positive (ALDH+) cell populations.…”

Section: Resultssupporting

confidence: 91%

“…A2780DR cells exhibited higher resistance to doxorubicin treatment than the parental A2780 cells (Supplementary Fig. S1), and our microarray analysis performed in the previous study 36 revealed that ALDH1A1 was the second highest gene to increase in A2780DR compared to A2780 (Table 1). Western blot analysis showed that the protein level for ALDH1A1 was higher in A2780DR than that in parental A2780 (Fig.…”

Section: Resultsmentioning

confidence: 52%

“…Predesigned ALDH1A1 siRNA (forward: 5′-GAGAGUACGGUUUCCAUGA-3′, reverse: 5′-UCAUGGAAACCGUACUCUC-3′) and a scrambled control siRNA 36,52 were purchased from the Bioneer Corporation (Daejeon, Republic of Korea). For transfection, 5×10 5 ALDH-H cells in 60-mm plates were incubated in Opti-MEM media (Hyclone, Logan, UT, USA) and transfected with the siRNAs using a Lipofectamine 2000 reagent (Life Technologies, Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

et al. 2018

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Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovarian CSCs. Our experimental system, ALDH1A1-high (ALDH-H) subpopulation, was isolated and stabilized using doxorubicin-resistant ovarian cancer A2780 cells. ALDH-H exerted CSC-like properties such as drug resistance, colony/sphere formation, and enhanced tumor growth along with high levels of CSCs markers compared to ALDH1A1-low (ALDH-L). Levels of NRF2 and subsequent target genes substantially increased in ALDH-H cells, and the increase in ALDH1A1 and p62 was associated with NRF2 upregulation. ALDH1A1-silencing blocked increases in NRF2, drug efflux transporters, and p62, along with CSC markers in ALDH-H cells. The inhibition of p62, which was elevated in ALDH-H, suppressed NRF2 activation. High NRF2 level was confirmed in the ALDH1-high subpopulation from colon cancer HCT116 cells. The functional implication of NRF2 activation in ovarian CSCs was verified by two experimental approaches. First, CSC-like properties such as high CSC markers, chemoresistance, colony/sphere formation, and tumor growth were significantly inhibited by NRF2-silencing in ALDH-H cells. Second, all-trans retinoic acid (ATRA) suppressed ALDH1 expression, inhibiting NRF2 activation, which led to the attenuation of CSC-like properties in ALDH-H cells but not in ALDH-L cells. These results provide insight into the molecular basis of the ALDH1A1-mediated development of CSC-like properties such as stress/treatment resistance, and further suggest the therapeutic potential of ATRA in ALDH-high ovarian CSCs.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

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High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

et al. 2018

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“…Erythropoietin is a hematopoietic hormone, and erythropoietin is known to inhibit sensitivity to PDT (17). Recent studies have revealed that tyrosine protein kinase Met (c-Met)/phosphoinositide 3-kinase (PI3K) signaling is related to resistance to PDT (18). Erythropoietin may induce resistance to PDT through the activation of c-Met/PI3K signaling.…”

Section: Signal -------------------------------------------------------mentioning

confidence: 99%

Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences

et al. 2017

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Abstract. Protoporphyrin IX (PpIX) levels are crucial to the antitumor action of photodynamic therapy (PDT). In the present study, the underling molecular mechanisms for the variation in PpIX levels in ovarian cancer cells were investigated. Five ovarian cancer cell lines were subcutaneously grafted onto the backs of nude mice. Once tumors had developed, 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA) was administered intraperitoneally and the tumor was irradiated twice/week. PpIX levels in the tumor were assayed using high-performance liquid chromatography. Enzymes involved in heme synthesis and degradation were screened using a microarray technique. Expression of the glutathione transferase Omega-1 (GSTO1) gene involved in the conversion of PpIX into heme in cells was quantified using the reverse transcription-quantitative polymerase chain reaction. In HTOA, HRA and DISS cells, PDT resulted in significant tumor shrinkage in comparison with the controls. In MCAS and TOV21G cells, no significant alterations in tumor growth were identified compared with the untreated cells. PpIX levels increased significantly in HTOA, DISS and HRA cells compared with in MCAS and TOV21G cells. A comparison of genetic profiles using PDT-sensitive DISS cells and PDT-resistant MCAS cells indicated that MCAS cells exhibited significantly increased levels of δ-aminolevulinate synthase (a rate-limiting enzyme in heme synthesis), heme oxygenase 2 (an enzyme that degrades heme into biliverdin), and biliverdin reductase B (an enzyme that reduces biliverdin into bilirubin) in comparison with DISS cells. The level of GSTO1 expression in HTOA, HRA and DISS cells was ~2.5-fold that in MCAS and TOV21G cells. Sensitivity to PDT is related to PpIX levels in cells. The results of the present study suggested that PpIX tends not to accumulate in PDT-resistant cells despite active heme synthesis and degradation, and that high levels of GSTO1 expression are associated with increased sensitivity to PDT. IntroductionThe standard treatment for ovarian cancer is surgery followed by anticancer therapy (1). A total of ~70% of advanced ovarian cancer recurs, so advanced ovarian cancer ultimately has a 5-year survival rate of between 30 and 40% (2). Ovarian cancer has the highest mortality rate among gynecological malignancies (3).Photodynamic therapy (PDT) has garnered attention as a novel therapy to reduce the tumor burden on a patient. PDT has been used to treat superficial esophageal cancer, early lung cancer and early gastric cancer (4-6). In gynecology, PDT has been used to treat early cancer of the cervix (7). Younger patients tend to opt to receive treatment that preserves fertility, and PDT may be such a treatment (7). Therefore, attention has focused on the usefulness of PDT in that regard. Unlike conventional approaches, PDT leaves the cervix intact, has a high cure rate, and does not hamper pregnancy or delivery following surgery (7).PDT is a therapy involving photosensitizers (or their precursors) with an affinity for tumors. The sp...

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“…Although Met kinase inhibitors such as cabozantinib, SAR125844, and tivantinib have been shown to be effective, resistance to Met kinase inhibitors develops rapidly (16)(17)(18). Therefore, interfering with the assembly of the HGF/SF-Met complex could constitute a new and promising route in the search for novel, cost-effective, and selective inhibitors of HGF/ SF-Met signaling, but it has its own challenges.…”

Section: Introductionmentioning

confidence: 99%

Developing Antagonists for the Met-HGF/SF Protein–Protein Interaction Using a Fragment-Based Approach

Winter

Sigurdardottir

DiCara

et al. 2016

Molecular Cancer Therapeutics

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In many cancers, aberrant activation of the Met receptor tyrosine kinase leads to dissociation of cells from the primary tumor, causing metastasis. Accordingly, Met is a high-profile target for the development of cancer therapies, and progress has been made through development of small molecule kinase inhibitors and antibodies. However, both approaches pose significant challenges with respect to either target specificity (kinase inhibitors) or the cost involved in treating large patient cohorts (antibodies). Here, we use a fragment-based approach in order to target the protein-protein interaction (PPI) between the a-chain of hepatocyte growth factor/scatter factor (HGF/SF; the NK1 fragment) and its high-affinity binding site located on the Met Sema domain. Surface plasmon resonance was used for initial fragment library screening and hits were developed into larger compounds using substructure (similarity) searches. We identified compounds able to interfere with NK1 binding to Met, disrupt Met signaling, and inhibit tumorsphere generation and cell migration. Using molecular docking, we concluded that some of these compounds inhibit the PPI directly, whereas others act indirectly. Our results indicate that chemical fragments can efficiently target the HGF/SF-Met interface and may be used as building blocks for generating biologically active lead compounds. This strategy may have broad application for the development of a new class of Met inhibitors, namely receptor antagonists, and in general for the development of small molecule PPI inhibitors of key therapeutic targets when structural information is not available.

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The c-MET/PI3K Signaling Is Associated with Cancer Resistance to Doxorubicin and Photodynamic Therapy by Elevating BCRP/ABCG2 Expression

Cited by 54 publications

References 58 publications

High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences

Developing Antagonists for the Met-HGF/SF Protein–Protein Interaction Using a Fragment-Based Approach

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