Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2

Hsieh, Yih‐Shou; Chu, Shu‐Chen; Yang, Shun‐Fa; Chen, Pei‐Ni; Liu, Yuchuan; Lu, Ko-Hsiu

doi:10.1093/carcin/bgl221

Cited by 104 publications

(125 citation statements)

References 43 publications

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“…We demonstrated that, silibinin could inhibit the migration and invasion of RCC cells induced by EGFR signaling via blocking of EGFR/MMP-9 signaling. However, two other EGFR signaling downstream proteins, STAT3 and AKT, were not affected by silibinin, which is in agreement with previous results that silibinin inhibited cell migration and invasion through ERK1/2 signal, not AKT and STAT3 phosphorylation (12,22,23).…”

Section: Discussionsupporting

confidence: 92%

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Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway

Liang

Zeng

et al. 2012

Oncol Rep

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Abstract. The activation of epidermal growth factor (EGF) through its receptor, EGFR, is one of the major mechanisms that mediate renal cell carcinoma (RCC) metastasis. Silibinin, a natural flavonoid antioxidant with pleiotropic anticancer capability, has shown anti-metastatic effects in a variety of cancers. However, the mechanism by which silibinin inhibits EGFR signal-induced migration and invasion of RCC cells is not clear. Here, we evaluated the potential roles of EGFR signaling cascade that affects RCC progression, and also investigated the inhibitory effect of silibinin on the EGFR signal-induced migration and invasion abilities of RCC cells. Our data indicated that silibinin inhibited migration and invasion of RCC cells in a dosedependent manner via blocking the EGFR signal, especially in the EGFR highly expressing RCC cells. Silibinin inhibited phosphorylation of EGFR and its downstream molecules ERK1/2 but did not affect phosphorylation of other downstream molecules, STAT3 and Akt, in human RCC cell lines. Moreover, our data suggested that silibinin significantly reduced the MMP-9 expression and its activity that was promoted by the EGFR signal, and also suppressed MMP9-dependent migration and invasion abilities of RCC cells. Taken together, this study clearly demonstrated that silibinin inhibited EGFR induced migration and invasion of RCC cells via blockade of EGFR/MMP-9 signaling. Thus, we suggest that silibinin could be used as a potential effective drug for the inhibition of RCC metastasis. IntroductionRenal cell carcinoma (RCC) accounted for 90-95% of neoplasms arising from the kidney and ~3.8% of adult malignancy in 2010 (1). Unfortunately, ~25-30% of patients have metastatic disease at first diagnosis, and >95% of these have multiple metastases (2). An aberrant activation of numerous signal pathways, including EGFR signal, has been recognized as a hallmark of cancer cell survival and progression (3). The studies also have revealed that overexpression of EGFR has been linked to RCC progression (4-6).Traditional systematic therapies for metastatic RCC tumors include immunotherapy, chemotherapy, and targeted therapy (7,8). However, low response rates have significantly retarded the efforts to improve the prognosis. There are still no effective methods for the treatment of metastatic RCC (9). Thus, searching for novel therapeutic methods or agents is needed for improving the efficacy against metastatic RCC.Acumulated evidence shows that silibinin, a natural flavonoid antioxidant, isolated from milk thistle (Silybum marianum), exerted pleiotropic anticancer capabilities in different human malignant tumors including prostate, bladder, breast, colon, and oral cancer (10-13). Due to the high efficacy of this drug against cancer as well as its non-toxic characteristics, the use of this drug provide a strong rationale for cancer prevention and adjuvant therapy compare with traditional chemical treatment.In our previous study, we found that silibinin inhibited cell proliferation in human RCC Caki-1 cells t...

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Section: Discussionsupporting

confidence: 92%

“…Besides its antiproliferative effect, silibinin also show antimetastatic effects on a variety of malignant tumors including prostate cancer, lung cancer, breast cancer, osteosarcoma and oral cancer (11)(12)(13)21,22). Still little is known about suppression effect of silibinin on EGFR signal-induced RCC migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway

Liang

Zeng

et al. 2012

Oncol Rep

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“…48 It is of fundamental importance that, to be clinically useful, the antineuropathic agents must reduce the neurotoxic effect of the chemotherapeutic agent maintaining its full anti-tumor efficacy. In this light, silibinin shows a cancer chemopreventive role in both in vitro 10,21 and in vivo 40,46 models. It modulates the imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis.…”

Section: Discussionmentioning

confidence: 98%

“…26 In addition, an anti-metastatic activity for silibinin has been also described. 11,21 A recent report of the USA National Toxicology Program 33 describes the results of repeated treatments of rats with sylibum marianum extract (containing 65% sylimarin, therefore 30-40% silibinin). 1 No toxic effects have been shown after daily per os administration of 2,500 mgkg À1 extract for 2 years.…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

Mannelli

Zanardelli

Failli

et al. 2012

The Journal of Pain

161

120

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Oxaliplatin is the standard treatment for advanced colorectal cancer. Its dose-limiting toxicity is the development of a painful neuropathic syndrome sustained by unclear mechanisms. Although the oxidative hypothesis is a matter of debate, direct data about oxidative damage induced in vivo by anticancer agents are lacking and the efficacy of the available antioxidant compounds are unsatisfactory. In a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg À1 i.p., daily for 21 days), we described an important component of oxidative stress. In the plasma of oxaliplatin-treated rats, the increases in carbonylated protein and thiobarbituric acid reactive substances were the index of the resultant protein oxidation and lipoperoxidation, respectively. The same pattern of oxidation was revealed also in the sciatic nerve, and in the spinal cord where the damage reached the DNA level. The antioxidant compound silibinin (100 mgkg À1 per os), administered once a day, starting from the first day of oxaliplatin injection until the 20th, prevented oxidative damage as did a-tocopherol. Repetitive administration of silibinin, as well as a-tocopherol, reduced oxaliplatin-dependent pain induced by mechanical and thermal stimuli. Antioxidants were also able to improve motor coordination. The antineuropathic effect of both molecules improved by about 50% oxaliplatin-induced behavioral alterations.Perspective: This study characterizes oxidative stress parameters in a rat model of oxaliplatininduced neuropathy. A relationship between the improvement of oxidative alterations and pain relief is established in rats treated with natural antioxidant compounds like a-tocopherol and silibinin. Silibinin could be a valid therapeutic option for chemotherapy-induced neuropathy.

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“…We therefore examined the role of AP-1 in CAGE-promoted cellular invasion. AP-1 plays many roles during cellular invasion, including as a down-http://bmbreports.org stream target of ERK (9) and as an inducer of MMP-2 in osteocarcinomas (10). AP-1 is further necessary for angiopoietinpromoted endothelial migration (11).…”

Section: Cage Induces Fra-1 By Activating Erk and Mmp-2 Through The Amentioning

confidence: 99%

Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2

Cited by 104 publications

References 43 publications

Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway

Inhibitory effect of silibinin on EGFR signal-induced renal cell carcinoma progression via suppression of the EGFR/MMP-9 signaling pathway

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

The cancer/testis antigen CAGE induces MMP-2 through the activation of NF-κB and AP-1

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