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Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma.

Hu W, Lu SX, Li M, Zhang C, Liu LL, Fu J, Jin JT, Luo RZ, Zhang CZ, Yun JP - Oncotarget (2015)

Bottom Line: PKM2 depletion decreased the degradation of Bim.Combination of PKM2 and Bim levels had the best prognostic significance.We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

ABSTRACT
Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

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PKM2 expression is reversely correlated with outcomes of HCC patientsThe HCC patients in the training (n = 490) and validation (n = 148) cohort were stratified according to the expression of PKM2. Kaplan–Meier analysis disclosed the relationship of PKM2 expression and the overall survival (A&D), disease-free survival (B&E) and recurrence probability (C&F) of HCC patients (log-rank test).
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Figure 2: PKM2 expression is reversely correlated with outcomes of HCC patientsThe HCC patients in the training (n = 490) and validation (n = 148) cohort were stratified according to the expression of PKM2. Kaplan–Meier analysis disclosed the relationship of PKM2 expression and the overall survival (A&D), disease-free survival (B&E) and recurrence probability (C&F) of HCC patients (log-rank test).

Mentions: The prognostic significance of PKM2 was also determined. Kaplan–Meier analysis indicated a significantly better prognosis in HCC cases with low PKM2 expression, in terms of overall survival (P < 0.0001), disease-free survival (P = 0.001) and recurrence-free survival (P = 0.007) in the training cohort. On the contrary, high PKM2 expression tended towards unfavorable prognosis (log-rank test, Figure 2A–2C). Consistently, increase of PKM2 was associated with inferior overall survival (P < 0.0001), disease-free survival (P = 0.0003) and recurrence-free survival (P < 0.0001) in the validation cohort (log-rank test; Figure 2D–2F). Multiple Cox regression analysis showed that PKM2 retained an independent factor for both overall survival and disease-free survival in both training and validation cohorts (Supplementary Table 3&4).


Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma.

Hu W, Lu SX, Li M, Zhang C, Liu LL, Fu J, Jin JT, Luo RZ, Zhang CZ, Yun JP - Oncotarget (2015)

PKM2 expression is reversely correlated with outcomes of HCC patientsThe HCC patients in the training (n = 490) and validation (n = 148) cohort were stratified according to the expression of PKM2. Kaplan–Meier analysis disclosed the relationship of PKM2 expression and the overall survival (A&D), disease-free survival (B&E) and recurrence probability (C&F) of HCC patients (log-rank test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466635&req=5

Figure 2: PKM2 expression is reversely correlated with outcomes of HCC patientsThe HCC patients in the training (n = 490) and validation (n = 148) cohort were stratified according to the expression of PKM2. Kaplan–Meier analysis disclosed the relationship of PKM2 expression and the overall survival (A&D), disease-free survival (B&E) and recurrence probability (C&F) of HCC patients (log-rank test).
Mentions: The prognostic significance of PKM2 was also determined. Kaplan–Meier analysis indicated a significantly better prognosis in HCC cases with low PKM2 expression, in terms of overall survival (P < 0.0001), disease-free survival (P = 0.001) and recurrence-free survival (P = 0.007) in the training cohort. On the contrary, high PKM2 expression tended towards unfavorable prognosis (log-rank test, Figure 2A–2C). Consistently, increase of PKM2 was associated with inferior overall survival (P < 0.0001), disease-free survival (P = 0.0003) and recurrence-free survival (P < 0.0001) in the validation cohort (log-rank test; Figure 2D–2F). Multiple Cox regression analysis showed that PKM2 retained an independent factor for both overall survival and disease-free survival in both training and validation cohorts (Supplementary Table 3&4).

Bottom Line: PKM2 depletion decreased the degradation of Bim.Combination of PKM2 and Bim levels had the best prognostic significance.We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

ABSTRACT
Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389-2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214-2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.

Show MeSH
Related in: MedlinePlus