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TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.

Hua F, Li K, Yu JJ, Lv XX, Yan J, Zhang XW, Sun W, Lin H, Shang S, Wang F, Cui B, Mu R, Huang B, Jiang JD, Hu ZW - Nat Commun (2015)

Bottom Line: Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion.TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation.Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.

ABSTRACT
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.

No MeSH data available.


Related in: MedlinePlus

Interrupting the TRB3/p62 interaction inhibits tumour development and progression.(a–c) Pep2–A2 treatment inhibits tumour growth. KK-Ay and C57 BL/6 mice were s.c. inoculated with B16-F10 cells (1.5 × 105). The animals were treated with Pep2–A2 or Pep2-con (5 mg kg−1) for indicated times. Data are tumour growth curves with mean volumes±s.e.m. at indicated times (a) representative graphs of mice (b) and tumours/quantified tumour weight (c; n=8 per group). Scale bar, 1 cm. (d) Pep2–A2 treatment inhibits metastasis. KK-Ay and C57 BL/6 mice were i.v. injected with B16-F10 cells (3 × 105) and treated with Pep2-con or Pep2–A2 (n=11 per group). Data are representative graphs of animals (left) and total tumour volumes (mean±s.e.m.) at multiple metastatic sites (right). (e–g) Pep2–A2 treatment induces a similar antitumour efficacy with TRB3 silence. BALB/c nude mice were i.v. (3 × 106) or s.c. (1 × 106) injected with HepG2 cells or HepG2 cells expressing TRB3-shRNA1. One week later, the mice injected with the HepG2 cells were treated with Pep2-con or Pep2–A2 (5 mg kg−1) twice a week for 5 weeks. Data are representative of bioluminescence imaging (n=8 per group) (e) Kaplan–Meier survival curves for indicated groups of mice (n=20 per group; statistical significance determined with Kaplan–Meier log-rank test) and (f) photographs of representative mice (n=8 per group). Scale bar, 1 cm. (g). Statistical significance was determined with Student's t-test; *P<0.05, **P<0.01, ***P<0.001. (h) Schematic diagram illustrates the role of TRB3 in metabolic stresses induced cancer development and progression.
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f9: Interrupting the TRB3/p62 interaction inhibits tumour development and progression.(a–c) Pep2–A2 treatment inhibits tumour growth. KK-Ay and C57 BL/6 mice were s.c. inoculated with B16-F10 cells (1.5 × 105). The animals were treated with Pep2–A2 or Pep2-con (5 mg kg−1) for indicated times. Data are tumour growth curves with mean volumes±s.e.m. at indicated times (a) representative graphs of mice (b) and tumours/quantified tumour weight (c; n=8 per group). Scale bar, 1 cm. (d) Pep2–A2 treatment inhibits metastasis. KK-Ay and C57 BL/6 mice were i.v. injected with B16-F10 cells (3 × 105) and treated with Pep2-con or Pep2–A2 (n=11 per group). Data are representative graphs of animals (left) and total tumour volumes (mean±s.e.m.) at multiple metastatic sites (right). (e–g) Pep2–A2 treatment induces a similar antitumour efficacy with TRB3 silence. BALB/c nude mice were i.v. (3 × 106) or s.c. (1 × 106) injected with HepG2 cells or HepG2 cells expressing TRB3-shRNA1. One week later, the mice injected with the HepG2 cells were treated with Pep2-con or Pep2–A2 (5 mg kg−1) twice a week for 5 weeks. Data are representative of bioluminescence imaging (n=8 per group) (e) Kaplan–Meier survival curves for indicated groups of mice (n=20 per group; statistical significance determined with Kaplan–Meier log-rank test) and (f) photographs of representative mice (n=8 per group). Scale bar, 1 cm. (g). Statistical significance was determined with Student's t-test; *P<0.05, **P<0.01, ***P<0.001. (h) Schematic diagram illustrates the role of TRB3 in metabolic stresses induced cancer development and progression.

Mentions: Indeed, the Pep2–A2 treatment attenuated tumour growth and metastasis in C57 BL/6 and KK-Ay mice inoculated with B16-F10 cells (Fig. 9a–d and Supplementary Table 5). We compared the antitumour role of TRB3 silencing or Pep2–A2 by using the nude mice i.v. injected with TRB3-silenced HepG2 cells or nude mice injected with control-shRNA HepG2 cells that were treated with Pep2–A2. We found that Pep2–A2 could attenuate pulmonary metastasis (Fig. 9e) and increase animal survival (Fig. 9f). In addition, Pep2–A2 inhibited tumour growth and decreased tumour sizes (Fig. 9g). Similar results were observed in nude mice inoculated with HCT-8 cells (Supplementary Fig. 7a,b). Finally, we examined whether Pep2–A2 inhibited primary recurrence and multiorgan metastasis after surgical resection of xenograft tumours. We found that Pep2–A2 as well TRB3 depletion inhibited tumour recurrence at primary location and multiple-organ metastasis (Supplementary Fig. 7c). Taken together, these results verify that interrupting the TRB3/p62 interaction produces a potent antitumour efficacy via restoring the p62 functions to speed the autophagy and UPS degradation (Fig. 9h).


TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.

Hua F, Li K, Yu JJ, Lv XX, Yan J, Zhang XW, Sun W, Lin H, Shang S, Wang F, Cui B, Mu R, Huang B, Jiang JD, Hu ZW - Nat Commun (2015)

Interrupting the TRB3/p62 interaction inhibits tumour development and progression.(a–c) Pep2–A2 treatment inhibits tumour growth. KK-Ay and C57 BL/6 mice were s.c. inoculated with B16-F10 cells (1.5 × 105). The animals were treated with Pep2–A2 or Pep2-con (5 mg kg−1) for indicated times. Data are tumour growth curves with mean volumes±s.e.m. at indicated times (a) representative graphs of mice (b) and tumours/quantified tumour weight (c; n=8 per group). Scale bar, 1 cm. (d) Pep2–A2 treatment inhibits metastasis. KK-Ay and C57 BL/6 mice were i.v. injected with B16-F10 cells (3 × 105) and treated with Pep2-con or Pep2–A2 (n=11 per group). Data are representative graphs of animals (left) and total tumour volumes (mean±s.e.m.) at multiple metastatic sites (right). (e–g) Pep2–A2 treatment induces a similar antitumour efficacy with TRB3 silence. BALB/c nude mice were i.v. (3 × 106) or s.c. (1 × 106) injected with HepG2 cells or HepG2 cells expressing TRB3-shRNA1. One week later, the mice injected with the HepG2 cells were treated with Pep2-con or Pep2–A2 (5 mg kg−1) twice a week for 5 weeks. Data are representative of bioluminescence imaging (n=8 per group) (e) Kaplan–Meier survival curves for indicated groups of mice (n=20 per group; statistical significance determined with Kaplan–Meier log-rank test) and (f) photographs of representative mice (n=8 per group). Scale bar, 1 cm. (g). Statistical significance was determined with Student's t-test; *P<0.05, **P<0.01, ***P<0.001. (h) Schematic diagram illustrates the role of TRB3 in metabolic stresses induced cancer development and progression.
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f9: Interrupting the TRB3/p62 interaction inhibits tumour development and progression.(a–c) Pep2–A2 treatment inhibits tumour growth. KK-Ay and C57 BL/6 mice were s.c. inoculated with B16-F10 cells (1.5 × 105). The animals were treated with Pep2–A2 or Pep2-con (5 mg kg−1) for indicated times. Data are tumour growth curves with mean volumes±s.e.m. at indicated times (a) representative graphs of mice (b) and tumours/quantified tumour weight (c; n=8 per group). Scale bar, 1 cm. (d) Pep2–A2 treatment inhibits metastasis. KK-Ay and C57 BL/6 mice were i.v. injected with B16-F10 cells (3 × 105) and treated with Pep2-con or Pep2–A2 (n=11 per group). Data are representative graphs of animals (left) and total tumour volumes (mean±s.e.m.) at multiple metastatic sites (right). (e–g) Pep2–A2 treatment induces a similar antitumour efficacy with TRB3 silence. BALB/c nude mice were i.v. (3 × 106) or s.c. (1 × 106) injected with HepG2 cells or HepG2 cells expressing TRB3-shRNA1. One week later, the mice injected with the HepG2 cells were treated with Pep2-con or Pep2–A2 (5 mg kg−1) twice a week for 5 weeks. Data are representative of bioluminescence imaging (n=8 per group) (e) Kaplan–Meier survival curves for indicated groups of mice (n=20 per group; statistical significance determined with Kaplan–Meier log-rank test) and (f) photographs of representative mice (n=8 per group). Scale bar, 1 cm. (g). Statistical significance was determined with Student's t-test; *P<0.05, **P<0.01, ***P<0.001. (h) Schematic diagram illustrates the role of TRB3 in metabolic stresses induced cancer development and progression.
Mentions: Indeed, the Pep2–A2 treatment attenuated tumour growth and metastasis in C57 BL/6 and KK-Ay mice inoculated with B16-F10 cells (Fig. 9a–d and Supplementary Table 5). We compared the antitumour role of TRB3 silencing or Pep2–A2 by using the nude mice i.v. injected with TRB3-silenced HepG2 cells or nude mice injected with control-shRNA HepG2 cells that were treated with Pep2–A2. We found that Pep2–A2 could attenuate pulmonary metastasis (Fig. 9e) and increase animal survival (Fig. 9f). In addition, Pep2–A2 inhibited tumour growth and decreased tumour sizes (Fig. 9g). Similar results were observed in nude mice inoculated with HCT-8 cells (Supplementary Fig. 7a,b). Finally, we examined whether Pep2–A2 inhibited primary recurrence and multiorgan metastasis after surgical resection of xenograft tumours. We found that Pep2–A2 as well TRB3 depletion inhibited tumour recurrence at primary location and multiple-organ metastasis (Supplementary Fig. 7c). Taken together, these results verify that interrupting the TRB3/p62 interaction produces a potent antitumour efficacy via restoring the p62 functions to speed the autophagy and UPS degradation (Fig. 9h).

Bottom Line: Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion.TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation.Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis.

View Article: PubMed Central - PubMed

Affiliation: Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.

ABSTRACT
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.

No MeSH data available.


Related in: MedlinePlus