357P - Targeting dual metabolic pathway specifically killed malignant lymphoma cells

Date 18 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Basic Science
Lymphomas
Presenter Ting Wang
Citation Annals of Oncology (2016) 27 (suppl_9): ix104-ix111. 10.1093/annonc/mdw586
Authors T. Wang, X. Shao, B. Xu, H. Huang, F. Chen
  • Hematology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200127 - Shanghai/CN

Abstract

Background

The metabolic reprogramming is a remarkably different metabolic character among tumor cells and is linked to higher proliferation, stronger resistance to chemotherapy, more adaptive survival advantages and aggressive tumor progression. Malignant tumor cells prefer glycolysis rather than aerobic oxidation even under aerobic surroundings. Furthermore, this altered metabolism is an active adjustment regulated by PI3K/Akt/mTOR pathway, HIF-1α and c-MYC in a reversible manner.

Methods

Raji and SU-DHL4 cells were treated with different concentrations of rapamycin or oligomycin alone or the two drugs in combination. Cell proliferation was detected by CCK-8. The mRNA and protein expression levels of oncogene C-myc, hypoxia inducible factor-1α (HIF-1α), as well as key enzymes and proteins related to glycolysis pathway including hexokinase II (HKII), lactic dehydrogenase (LDHA) and succinate dehydrogenase (SDHA) were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. Glucose consumption and lactic acid generation were examined by Glucose (hexokinase, HK) Assay Kit and Lactate Assay Kit, respectively. Apoptosis and cell cycle distribution were analyzed by FCM.

Results

The mTORC1 inhibitor rapamycin (RAPA) and the proteasome inhibitor bortezomib (BTZ) hampered glycolysis in malignant B-cell lymphoma cells successfully. Either glycolysis inhibitors RAPA and BTZ or the aerobic oxidation inhibitor oligomycin (OM) selectively inhibited the proliferation of Raji and SU-DHL4 cells in a dose-dependent manner. In contrast, no difference was observed in normal lymphocytes. Furthermore, rapamycin and oligomycin combined with doxorubicin or bortezomib in combination with oligomycin, indicating attenuating both the glycolysis and the aerobic oxidation pathway at the same time, synergistically inhibited cell proliferation and induced cell apoptosis, and thus increased the sensitivity of malignant B-cell lymphoma cells toward doxorubicin and bortezomib, via blocking the dual metabolism. Synergistically inhibition on mRNAs and proteins (HIF-1α, HKII, LDHA, SDHA) was involved.

Conclusions

Inhibiting the dual metabolic pathway may provide a novel strategy to cure malignant B-cell lymphoma.

Clinical trial indentification

Legal entity responsible for the study

Renji Hospital, Shanghai Jiaotong University School of Medicine

Funding

National Natural Science Foundation of China (NSFC), Grant 81172253, Grant 81570177

Disclosure

All authors have declared no conflicts of interest.