Cripto-1 promotes resistance to drug-induced apoptosis by activating the TAK-1/NF-κB/survivin signaling pathway

Zhang, YingYu; Mi, Xuguang; Li, YuXin; YingShi,; Niu, Junqi

doi:10.1016/j.biopha.2018.05.063

Cited by 15 publications

(12 citation statements)

References 31 publications

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“…This brings up the possibility of a novel pathway involving secreted CRIPTO that may allow secreted CRIPTO to have less of an effect than membrane bound CRIPTO. Interestingly, it has recently been demonstrated that membrane-associated CRIPTO, but not soluble CRIPTO, promotes resistance to druginduced apoptosis [34].…”

Section: Discussionmentioning

confidence: 99%

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

et al. 2020

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Background: Adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC) and often harbors oncogenic driver mutations in the epidermal growth factor receptor (EGFR). Osimertinib (AZD9291), a third generation EGFR TKI, has replaced earlier generation EGFR TKIs for first line treatment of EGFR mutant lung cancer due to its improved overall survival, longer progression free survival, and better tolerability compared to earlier generation inhibitors. However, like earlier generation EGFR TKIs, only about two thirds of patients respond, indicating an unknown mechanism of intrinsic resistance for the non-responders. We previously identified overexpression of CRIPTO as a potential mechanism of intrinsic resistance to EGFR TKIs of first and second generation. Objective: To determine if CRIPTO could promote drug resistance against the third generation EGFR-TKIs osimertinib. We also wanted to investigate whether this resistance was conferred by both membrane bound and secreted CRIPTO. Finally, we wanted to explore the potential of secreted CRIPTO as a non-invasive biomarker for EGFR-TKI resistance. Materials and methods: HCC827 and H1975, EGFR mutant non-small cell lung carcinoma (NSCLC) cell lines, were transfected with wildtype CRIPTO, two secreted variants of CRIPTO, a membrane only version of CRIPTO, and the mock backbone vector as the control. Western blotting, immunoprecipitation, and in vitro viability experiments were performed. In vivo work was carried out in athymic nude mice; 2 × 10 6 CRIPTO overexpressing HCC827 cells were implanted per mouse. EGFR mutant NSCLC patient blood samples were collected before treatment with and EGFR-TKI, during response while on treatment, and at progression while on treatment. Results: Although both membrane bound and secreted CRIPTO forms were able to activate downstream pathways such as SRC, CRIPTO was unable to elicit resistance towards osimertinib in vitro or in vivo. CRIPTO serum levels in mice were higher in larger xenograft tumors. Furthermore, CRIPTO serum levels were higher in patients with progressing lung cancer when compared to their CRIPTO serum levels during EGFR-TKI response. Conclusions: CRIPTO does not cause resistance against third generation EGFR-TKI osimertinib. CRIPTO levels in serum might be a potentially useful biomarker for tumor burden in NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

et al. 2020

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“…Furthermore, CRIPTO expression has been shown to be involved in the activation of the well-known SMAD pathways, which could promote fibrogenesis and eventually HCC formation [ 33 , 57 , 60 ] and regulate the cardiac fibrotic response [ 61 ]. It has been shown that inducing cell damage to HepG2 cells leads to the upregulation of CRIPTO, which initiates apoptotic resistance and increased proliferation via NF-κB/Survivin pathways [ 62 ]. A similar mode of CRIPTO reactivation may occur in vivo, in which CRIPTO may become re-expressed as a response to cellular injury in order to promote tissue regeneration by orchestrating the reactivation of both fibrogenic cells and of quiescent hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis

Karkampouna

Helm

Scarpa

et al. 2021

Cells

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Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (αSMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of αSMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (αSMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in αSMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the αSMA expression. Temporal expression of CRIPTO in αSMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis. Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration.

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“…Due to the very high tumor expression of Cripto‐1 compared with normal tissue, Cripto‐1 has been targeted for cancer treatment with expectations of minimal impact on normal tissue. Indeed, there is a rationale for its use in combination with existing treatments as high Cripto‐1 expression may be responsible for resistant to certain treatments based on pre‐clinical studies with sorafenib, cytarabine, cisplatin, and taxol 228,237 . In at least one case, Cripto‐1 has been attributed to this by causing resistance to apoptosis via activation of a TAK‐1/NF‐κB/Survivin pathway 237 .…”

Section: Tgf‐β Superfamily Co‐receptors and Their Role In Cancermentioning

confidence: 99%

“…Indeed, there is a rationale for its use in combination with existing treatments as high Cripto‐1 expression may be responsible for resistant to certain treatments based on pre‐clinical studies with sorafenib, cytarabine, cisplatin, and taxol 228,237 . In at least one case, Cripto‐1 has been attributed to this by causing resistance to apoptosis via activation of a TAK‐1/NF‐κB/Survivin pathway 237 . However, it should be considered that Cripto‐1 expression in cancer cells can be heterogeneous with high and low expressing populations, and the low expressing populations have the potential to become high expressing, suggesting a level a plasticity that may add to the complexity of treatments targeting Cripto‐1 long‐term 231 …”

Section: Tgf‐β Superfamily Co‐receptors and Their Role In Cancermentioning

confidence: 99%

TGF‐β superfamily co‐receptors in cancer

Pawlak

Blobe

2021

Developmental Dynamics

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Transforming growth factor‐β (TGF‐β) superfamily signaling via their cognate receptors is frequently modified by TGF‐β superfamily co‐receptors. Signaling through SMAD‐mediated pathways may be enhanced or depressed depending on the specific co‐receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co‐receptors from the membrane to generate soluble forms that are often antagonistic to the membrane‐bound receptors. The co‐receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto‐1, MuSK, and RGMs. Dysregulation of these co‐receptors can lead to altered TGF‐β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF‐β superfamily co‐receptors on TGF‐β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co‐receptors.

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Cripto-1 promotes resistance to drug-induced apoptosis by activating the TAK-1/NF-κB/survivin signaling pathway

Cited by 15 publications

References 31 publications

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis

TGF‐β superfamily co‐receptors in cancer

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