Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer

Zhang, P; Shi, Bizhi; Zhou, Min; Jiang, Hua; Zhang, H; Pan, Xiaorong; Gao, Huile; Sun, Hao; Li, Z

doi:10.1038/cddis.2013.526

Cited by 87 publications

(95 citation statements)

References 36 publications

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“…Furthermore, we also showed that down-regulation of galectin-1 suppressed migratory and invasive abilities of HuH-7 R cells, and restored sorafenib sensitivity. Several studies supported that galectin-1 associated with metastatic ability and effects of galectin-1 knockdown on drug sensitivity in different types of cancer (42)(43)(44). Taken together, our findings indicate that galectin-1 may be a component of the mechanism that promotes the progression of HCC and resistance to sorafenib.…”

Section: Discussionsupporting

confidence: 80%

Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

Yeh¹,

Hsu

Shao

et al. 2015

Molecular & Cellular Proteomics

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Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7 R ) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7 R tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7 R cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1␣ signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy. Molecular & Cellular

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Section: Discussionsupporting

confidence: 80%

Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

Yeh¹,

Hsu

Shao

et al. 2015

Molecular & Cellular Proteomics

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“…24,25 This seems contradictory, however, in lung and ovarian cancer, gal-1 overexpression appears to promote chemotherapy resistance and downregulation of gal-1 expression can sensitize tumor cells to platin-based chemotherapy. 14,26,27 In ovarian cancer, gal-1 could possibly mediate these effects through activation of the H-Ras/Raf-1/ERK pathway. 14 The group of Le Mercier et al suggested that increased gal-1 levels therefore seem to be representative of defense mechanisms against cytotoxic drugs, such as chemotherapy, and that gal-1 could consequently be of major importance in chemotherapy resistance.…”

Section: Discussionmentioning

confidence: 99%

“…14,26,27 In ovarian cancer, gal-1 could possibly mediate these effects through activation of the H-Ras/Raf-1/ERK pathway. 14 The group of Le Mercier et al suggested that increased gal-1 levels therefore seem to be representative of defense mechanisms against cytotoxic drugs, such as chemotherapy, and that gal-1 could consequently be of major importance in chemotherapy resistance. 24 Both our results in gal-1 (increase after chemotherapy and being an independent prognostic factor) support this theory.…”

Section: Discussionmentioning

confidence: 99%

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Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

et al. 2016

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Neoplastic cells can escape immune control leading to cancer growth. Regulatory T cells (Treg), myeloidderived suppressor cells (MDSC) and tumor-associated macrophages (TAM) are crucial in immune escape. TAM are divided based on their immune profile, M1 are immunostimulatory while M2 are immunosuppressive. Research so far has mainly focused on the intratumoral behavior of these cells. This study, on the other hand, explored the systemic changes of the key metabolites [IL-4 (interleukin), IL-13, arginase, IL-10, VEGF-A (vascular endothelial growth factor), CCL-2 (chemokine (C-C) motif ligand 2) and TGF-b (transforming growth factor)] linked to Treg, MDSC and TAM during the course of the disease in ovarian and fallopian tube cancer patients. Serum samples were therefore analyzed at diagnosis, after (interval)-debulking surgery and after chemotherapy (paclitaxel-carboplatin). We also determined galectin-1 (gal-1), involved in angiogenesis and tumor-mediated immune evasion. We found significantly lower levels of IL-10, VEGF-A, TGF-b and arginase and higher levels of gal-1 after chemotherapy compared to diagnosis. After debulking surgery, a decrease in IL-10 was significant. Gal-1 and CCL-2 appeared independent prognostic factors for progression-free and overall survival (OS) (multivariate analysis). These results will help us in the decision making of future therapies in order to further modulate the immune system in a positive way.

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“…Given that Gal-1 could be such a strong potentiator of SPRED activity, it is interesting that typically higher Gal-1 levels are associated with a worse outcome in cancer (80,81). This would put the apparently small loss in K-ras inhibition, and also the increase in H-ras signaling due to SPRED loss-of-function mutations, in the spotlight of cancer progression.…”

Section: Discussionmentioning

confidence: 99%

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

Siljamäki

Abankwa

2016

Molecular and Cellular Biology

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The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B-and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras-and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner.S PRED (Sprouty-related proteins with an EVH1 domain) proteins are Sprouty-related negative modulators of Ras/mitogen-activated protein kinase (MAPK) signaling, and they have been shown to attenuate extracellular signal-regulated kinase (ERK) activity following various extracellular mitogenic stimuli (e.g., growth factors, cytokines, and chemokines) (1-5). The mammalian SPRED family contains four members, SPRED1, SPRED2, SPRED3, and Eve-3, the last of which is a splice variant of SPRED3 (1, 2, 6). SPRED1 and SPRED2 proteins contain an N-terminal enabled/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain and a cysteine-rich C-terminal Sprouty-related (SPR) domain, separated by a small c-Kit-binding domain (KBD) (2, 7). The SPR domain is necessary for membrane anchoring following growth factor stimulation (5), and both EVH1 and SPR domains have been implicated in ERK suppression (5,8,9). SPRED3 lacks a functional KBD and shows lower inhibitory activity than SPRED1 and -2, suggesting that the KBD also participates in inhibiting ERK activity (1-5).The precise mechanism of action of how SPRED proteins block MAPK signaling remains unclear. Overexpression of SPRED1 was suggested to increase the recruitment of the Ras effector Raf to the plasma membrane, where its association with Ras does not, however, lead to Raf activation (1, 2, 6). Instead, SPRED1 was reported to prolong Ras-Raf complexation, thus withdrawing Raf from activation by phosphorylation (2, 7). Another study showed that overexpression of SPRED1 inhibits Ras activation, as evidenced by decreased levels of GTP-bound ...

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Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer

Cited by 87 publications

References 36 publications

Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

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