p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy‐induced apoptosis

Coltella, Nadia; Rasola, Andrea; Nano, Elisa; Bardella, Chiara; Fassetta, Michela; Filigheddu, Nicoletta; Graziani, Andrea; Comoglio, Paolo M.

doi:10.1002/ijc.21766

Cited by 35 publications

(60 citation statements)

References 53 publications

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“…Though it has been reported that in some experimental conditions including long-term pretreatment (48 h or more) with HGF, 46,47 HGF sensitizes ovarian carcinoma cell lines to cisplatin and paclitaxel mediated by p38 mitogen-activated protein kinase, it is worth noting that HGF does not induce apoptosis by itself, indicating that this role is to facilitate apoptosis triggered by the chemotherapeutic agents. 48 Our data are consistent with that HGF protects cells from apoptosis induced by chemotherapeutic agents, radiation, growth factor deprivation, etc in most physiologic and pathologic scenarios.…”

Section: Discussionmentioning

confidence: 99%

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

Uddin

Bavi

et al. 2011

Laboratory Investigation

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The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P ¼ 0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P ¼ 0.0008) and Bcl-XL (P ¼ 0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC.

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Section: Discussionmentioning

confidence: 99%

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

Uddin

Bavi

et al. 2011

Laboratory Investigation

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“…These results were confirmed in other cell types, including liver and lung myofibroblasts 133,159 and breast carcinoma cell lines 160 , in which HGF-induced apoptosis was attributed to the activation of protein kinase C and Jun amino-terminal kinase (JNK) or to the induction of reactive oxygen species. In ovarian cancer cells that have been treated with conventional chemotherapeutics, HGF enhances apoptosis through a p38 mitogen-activated protein kinase (MAPK)-dependent pathway 73,74 . The mechanism by which MET (also known as HGF receptor) activation leads to opposite outcomes -survival by default and apoptosis in restricted cellular contexts -has been only partially elucidated.…”

Section: Competing Interests Statementmentioning

confidence: 99%

“…2a). Following MET-dependent stimulation, the JNKs and p38s control a range of cellular processes as diverse as cell proliferation, differentiation, transformation and apoptosis 70,71,72,73,74 .…”

mentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

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1,043

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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“…For example, activation of Akt is believed to protect taxol-induced apoptosis, 23 while stimulation of the p38MAPK pathway leads to increased sensitivity to taxol. 24 Next we investigated the involvement of Akt and p38MAPK in the TWIST-mediated taxol resistance. As shown in Figure 2a, activation of p-Akt and suppression of p-p38MAPK, evidenced by alterations of phosphorylated protein expression, were observed in HNE1-T3 cells compared to HNE1 cells.…”

Section: Role Of Akt and P38map Kinases In Twist-mediated Taxol Resismentioning

confidence: 99%

Anti‐apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells

Zhang

Wang

Ling

et al. 2007

Intl Journal of Cancer

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TWIST, a basic helix-loop-helix transcription factor, has been reported to be associated with development and progression of human cancer. Recently, over expression of TWIST is found in cancer patients with shorter survival and poor response to chemotherapy. Previously, we found that upregulation of TWIST was responsible for the development of acquired resistance to taxol in a nasopharyngeal carcinoma (NPC) cell line, HNE1-T3 (Wang et al., Oncogene, 2004;24:274). In this study, we investigated the underlying molecular mechanisms responsible for the TWIST-mediated taxol resistance. By comparison of the parental HNE1 and its derivative HNE1-T3 cell lines, we found that the resistance to taxol in HNE1-T3 cells was associated with suppression of taxol-induced apoptosis evidenced by decreased expression of Bak and Bax and increased Bcl-2, as well as inhibition of PARP and caspase cleavage and DNA ladder formation. However, there was no correlation between taxol sensitivity and alterations on G2/M cell cycle distribution, suggesting that the TWIST-induced taxol resistance is mediated through protection against apoptosis but not mitotic arrest. Analysis of additional 8 NPC cell lines showed that upregulation of TWIST was associated with resistance to microtubule disrupting agents, especially taxol, and inactivation of TWIST through small RNA interference led to increased sensitivity to taxol-induced cell death. Subsequent studies also demonstrated that the TWIST-mediated taxol resistance may be regulated through its positive involvement with the Akt pathway. Our findings suggest an underlying molecular mechanism responsible for the TWIST-mediated chemodrug resistance and suggest a target for overcoming taxol resistance in cancer cells. ' 2007 Wiley-Liss, Inc.

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p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy‐induced apoptosis

Cited by 35 publications

References 53 publications

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

MET signalling: principles and functions in development, organ regeneration and cancer

Anti‐apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells

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