Limits...
Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer.

Wei TT, Lin YC, Lin PH, Shih JY, Chou CW, Huang WJ, Yang YC, Hsiao PW, Chen CC - Oncotarget (2015)

Bottom Line: Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens.HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl.Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

ABSTRACT
Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens. HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl. Ectopic expression of c-Cbl induced decreased EGFR, inhibited growth in NSCLC cells. Knockdown of EGFR inhibited NSCLC growth. Mutation of EGFR at Y1045 decreased WJ-induced growth inhibition as well as in vivo anti-cancer effect and EGFR degradation mediated by WJ. Time-lapse confocal analysis showed co-localization of c-Cbl and EGFR after WJ treatment. Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models. C-Cbl up-regulation induced by HDACi is a potential strategy for NSCLC treatment.

No MeSH data available.


Related in: MedlinePlus

WJ inhibited lung tumor growth in a tail vein injected mouse modelMale NOD/SCID mice were intravenously injected with CL1-5 cells (2.5 × 106) through tail vein. WJ was intraperitoneally injected at day 21 on days 1, 3 and 5 for two weeks. All mice were sacrificed at 5 weeks and lung segments were fixed by formalin. A, Schematic overview of WJ administration (upper left panel). Numbers of tumor nodules per mouse (upper right panel). *P <0.05, **P <0.01 versus vehicle. Gross pictures and H&E stains of lungs (lower panel). The arrowhead indicates the macroscopic lesions (scale bar: 5 mm). B, Effect of WJ and SAHA on PARP cleavage, EGFR signaling pathway and protein acetylation in lung tumor tissues. Total cell lysates were prepared and western blot was performed using indicated antibodies. C, Lung tissues were immunostained with anti-c-Cbl or anti-EGFR antibody and representive results were shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494952&req=5

Figure 5: WJ inhibited lung tumor growth in a tail vein injected mouse modelMale NOD/SCID mice were intravenously injected with CL1-5 cells (2.5 × 106) through tail vein. WJ was intraperitoneally injected at day 21 on days 1, 3 and 5 for two weeks. All mice were sacrificed at 5 weeks and lung segments were fixed by formalin. A, Schematic overview of WJ administration (upper left panel). Numbers of tumor nodules per mouse (upper right panel). *P <0.05, **P <0.01 versus vehicle. Gross pictures and H&E stains of lungs (lower panel). The arrowhead indicates the macroscopic lesions (scale bar: 5 mm). B, Effect of WJ and SAHA on PARP cleavage, EGFR signaling pathway and protein acetylation in lung tumor tissues. Total cell lysates were prepared and western blot was performed using indicated antibodies. C, Lung tissues were immunostained with anti-c-Cbl or anti-EGFR antibody and representive results were shown.

Mentions: To further examine the activity of WJ, CL1-5 cells were intravenously injected into NOD/SCID mice via the tail vein. Lung tumor nodules were evident three weeks after injection (Figure 5A). WJ was more potent than SAHA to inhibit tumor growth, which was confirmed by H&E staining (Figure 5A). WJ did not exhibit toxicity in various organs by microscopic evaluation (Supplementary Figure S3). Induction of c-Cbl accompanied with EGFR degradation in the lung tissues was evident by western blot and immunohistochemistry analysis (Figure 5B and 5C). WJ also reduced phosphorylations of EGFR and its downstream AKT and ERK accompanied with inducing PARP cleavage (Figure 5B). Acetylations of histone H3 and tubulin were confirmed (Figure 5B).


Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer.

Wei TT, Lin YC, Lin PH, Shih JY, Chou CW, Huang WJ, Yang YC, Hsiao PW, Chen CC - Oncotarget (2015)

WJ inhibited lung tumor growth in a tail vein injected mouse modelMale NOD/SCID mice were intravenously injected with CL1-5 cells (2.5 × 106) through tail vein. WJ was intraperitoneally injected at day 21 on days 1, 3 and 5 for two weeks. All mice were sacrificed at 5 weeks and lung segments were fixed by formalin. A, Schematic overview of WJ administration (upper left panel). Numbers of tumor nodules per mouse (upper right panel). *P <0.05, **P <0.01 versus vehicle. Gross pictures and H&E stains of lungs (lower panel). The arrowhead indicates the macroscopic lesions (scale bar: 5 mm). B, Effect of WJ and SAHA on PARP cleavage, EGFR signaling pathway and protein acetylation in lung tumor tissues. Total cell lysates were prepared and western blot was performed using indicated antibodies. C, Lung tissues were immunostained with anti-c-Cbl or anti-EGFR antibody and representive results were shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494952&req=5

Figure 5: WJ inhibited lung tumor growth in a tail vein injected mouse modelMale NOD/SCID mice were intravenously injected with CL1-5 cells (2.5 × 106) through tail vein. WJ was intraperitoneally injected at day 21 on days 1, 3 and 5 for two weeks. All mice were sacrificed at 5 weeks and lung segments were fixed by formalin. A, Schematic overview of WJ administration (upper left panel). Numbers of tumor nodules per mouse (upper right panel). *P <0.05, **P <0.01 versus vehicle. Gross pictures and H&E stains of lungs (lower panel). The arrowhead indicates the macroscopic lesions (scale bar: 5 mm). B, Effect of WJ and SAHA on PARP cleavage, EGFR signaling pathway and protein acetylation in lung tumor tissues. Total cell lysates were prepared and western blot was performed using indicated antibodies. C, Lung tissues were immunostained with anti-c-Cbl or anti-EGFR antibody and representive results were shown.
Mentions: To further examine the activity of WJ, CL1-5 cells were intravenously injected into NOD/SCID mice via the tail vein. Lung tumor nodules were evident three weeks after injection (Figure 5A). WJ was more potent than SAHA to inhibit tumor growth, which was confirmed by H&E staining (Figure 5A). WJ did not exhibit toxicity in various organs by microscopic evaluation (Supplementary Figure S3). Induction of c-Cbl accompanied with EGFR degradation in the lung tissues was evident by western blot and immunohistochemistry analysis (Figure 5B and 5C). WJ also reduced phosphorylations of EGFR and its downstream AKT and ERK accompanied with inducing PARP cleavage (Figure 5B). Acetylations of histone H3 and tubulin were confirmed (Figure 5B).

Bottom Line: Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens.HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl.Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

ABSTRACT
Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens. HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl. Ectopic expression of c-Cbl induced decreased EGFR, inhibited growth in NSCLC cells. Knockdown of EGFR inhibited NSCLC growth. Mutation of EGFR at Y1045 decreased WJ-induced growth inhibition as well as in vivo anti-cancer effect and EGFR degradation mediated by WJ. Time-lapse confocal analysis showed co-localization of c-Cbl and EGFR after WJ treatment. Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models. C-Cbl up-regulation induced by HDACi is a potential strategy for NSCLC treatment.

No MeSH data available.


Related in: MedlinePlus