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Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.

Zhang Y, Qu X, Teng Y, Li Z, Xu L, Liu J, Ma Y, Fan Y, Li C, Liu S, Wang Z, Hu X, Zhang J, Liu Y - Oncotarget (2015)

Bottom Line: The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function.However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

ABSTRACT
The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.

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Cbl-b prolonged remission and disease-specific survival in P-gp positive breast cancer patients treated with a Dox-based regimen(A) Immunohistochemistry images of tissue sections stained against Cbl-b and P-gp. a–d shows breast tissue negatively and positively stained with anti-Cbl-b antibody; e–h show breast tissue negatively and positively stained with anti-P-gp antibody. (B) Disease-specific survival rates of patients with P-gp positive breast cancer positive or negative for Cbl-b were estimated with the Kaplan–Meier method and log-rank test; n = 121, P < 0.05. (C) Proposed model showing that c-Src dependent Cav-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in MDR. In a negative feedback loop, Cbl-b translocated from the nucleus to the cytoplasm, preventing the translocation of P-gp into caveolae and reversed MDR by ubiquitinating c-Src and targeting it for degradation.
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Figure 6: Cbl-b prolonged remission and disease-specific survival in P-gp positive breast cancer patients treated with a Dox-based regimen(A) Immunohistochemistry images of tissue sections stained against Cbl-b and P-gp. a–d shows breast tissue negatively and positively stained with anti-Cbl-b antibody; e–h show breast tissue negatively and positively stained with anti-P-gp antibody. (B) Disease-specific survival rates of patients with P-gp positive breast cancer positive or negative for Cbl-b were estimated with the Kaplan–Meier method and log-rank test; n = 121, P < 0.05. (C) Proposed model showing that c-Src dependent Cav-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in MDR. In a negative feedback loop, Cbl-b translocated from the nucleus to the cytoplasm, preventing the translocation of P-gp into caveolae and reversed MDR by ubiquitinating c-Src and targeting it for degradation.

Mentions: We also determined whether Cbl-b expression was associated with the clinical outcomes of patients with breast cancer. To this end, tumor samples from 211 breast cancer patients were collected for immunohistochemistry using anti-Cbl-b and anti-P-gp antibodies (Figure 6A). The levels of P-gp had no significant influence on survival in cancer patients undergoing chemotherapy (Supplementary Figure 4, available online). Survival analysis was performed in 121 patient samples (37.9%) that were positive for P-gp, which showed a statistically significant difference in disease-free survival (DFS) and disease-specific survival (DSS) between 73 patients whose tumors were positive for Cbl-b expression and 48 patients whose tumors were negative for Cbl-b expression as estimated with the Kaplan–Meier method and log-rank test (Table 1, Figure 6B). Our results indicate that decreased expression of Cbl-b is associated with poor prognosis in patients with drug resistant breast cancer. Taken together, these findings suggest that Cbl-b may play a role in tumor MDR.


Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.

Zhang Y, Qu X, Teng Y, Li Z, Xu L, Liu J, Ma Y, Fan Y, Li C, Liu S, Wang Z, Hu X, Zhang J, Liu Y - Oncotarget (2015)

Cbl-b prolonged remission and disease-specific survival in P-gp positive breast cancer patients treated with a Dox-based regimen(A) Immunohistochemistry images of tissue sections stained against Cbl-b and P-gp. a–d shows breast tissue negatively and positively stained with anti-Cbl-b antibody; e–h show breast tissue negatively and positively stained with anti-P-gp antibody. (B) Disease-specific survival rates of patients with P-gp positive breast cancer positive or negative for Cbl-b were estimated with the Kaplan–Meier method and log-rank test; n = 121, P < 0.05. (C) Proposed model showing that c-Src dependent Cav-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in MDR. In a negative feedback loop, Cbl-b translocated from the nucleus to the cytoplasm, preventing the translocation of P-gp into caveolae and reversed MDR by ubiquitinating c-Src and targeting it for degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466646&req=5

Figure 6: Cbl-b prolonged remission and disease-specific survival in P-gp positive breast cancer patients treated with a Dox-based regimen(A) Immunohistochemistry images of tissue sections stained against Cbl-b and P-gp. a–d shows breast tissue negatively and positively stained with anti-Cbl-b antibody; e–h show breast tissue negatively and positively stained with anti-P-gp antibody. (B) Disease-specific survival rates of patients with P-gp positive breast cancer positive or negative for Cbl-b were estimated with the Kaplan–Meier method and log-rank test; n = 121, P < 0.05. (C) Proposed model showing that c-Src dependent Cav-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in MDR. In a negative feedback loop, Cbl-b translocated from the nucleus to the cytoplasm, preventing the translocation of P-gp into caveolae and reversed MDR by ubiquitinating c-Src and targeting it for degradation.
Mentions: We also determined whether Cbl-b expression was associated with the clinical outcomes of patients with breast cancer. To this end, tumor samples from 211 breast cancer patients were collected for immunohistochemistry using anti-Cbl-b and anti-P-gp antibodies (Figure 6A). The levels of P-gp had no significant influence on survival in cancer patients undergoing chemotherapy (Supplementary Figure 4, available online). Survival analysis was performed in 121 patient samples (37.9%) that were positive for P-gp, which showed a statistically significant difference in disease-free survival (DFS) and disease-specific survival (DSS) between 73 patients whose tumors were positive for Cbl-b expression and 48 patients whose tumors were negative for Cbl-b expression as estimated with the Kaplan–Meier method and log-rank test (Table 1, Figure 6B). Our results indicate that decreased expression of Cbl-b is associated with poor prognosis in patients with drug resistant breast cancer. Taken together, these findings suggest that Cbl-b may play a role in tumor MDR.

Bottom Line: The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function.However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

ABSTRACT
The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.

Show MeSH
Related in: MedlinePlus