Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo

Mao, Meng; Wang, Huan Huan; Guo, Wen; Wu, Zhaojun; Zeng, Xian; Zaorsky, Nicholas G.; Shi, Hua; Dong, Qian; Niu, Zhi Min; Jiang, Bo; Zhao, Lu; Yuan, Zhi Yong; Wang, Ping

doi:10.1016/j.canlet.2014.11.016

Cited by 57 publications

(43 citation statements)

References 56 publications

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“…Other studies have reported that the glycolytic pathway and the expression of glycolytic enzymes are associated with cancer radiosensitivity (26,27). We showed that ALDOA expression is positively correlated with the activity of glycolysis, with cell cycle progression and with ROS production.…”

Section: Discussionsupporting

confidence: 57%

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Kawai

Uemura

Munakata

et al. 2016

International Journal of Oncology

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Abstract.Hypoxia is an essential feature of cancer malignancy, but there are no methods for the routine detection of hypoxiainducible prognostic factors and potential therapeutic targets. We reported previously that the hypoxic tumor cells of metastatic liver tissue from patients with colorectal cancer (CRC) could be used as an 'in vivo' hypoxia culture model. Several potential hypoxia-inducible genes were identified using this model. Among them, one glycolytic enzyme was of special interest. There is currently increasing attention on glycolytic enzymes as potential therapeutic targets due to their association with cancer-specific metabolism. To better understand the molecular mechanisms of cancer malignancy, we investigated the expression of fructose-bisphosphate aldolase A (ALDOA) and its relationship with cancer metabolism. We found that ALDOA was induced by hypoxia in CRC-derived cell lines, and univariate and multivariate analyses of microarray data from the resected CRC samples of 222 patients revealed that ALDOA was an independent prognostic factor for CRC. We also analyzed the malignant potential of ALDOA in vitro using overexpression and knockdown assays. We found that ALDOA was negatively related to chemosensitivity and radiosensitivity and positively associated with proliferation, sphere formation and invasion in both normoxia and hypoxia. These associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxiainducible prognostic factor that is closely related to CRC malignancy, and also provide new insights into the importance of ALDOA and glycolysis in cancer and suggest new targets for anticancer therapies.

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Section: Discussionsupporting

confidence: 57%

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Kawai

Uemura

Munakata

et al. 2016

International Journal of Oncology

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“…A few studies have demonstrated that the Warburg effect contributes to the radioresistance of various malignant tumors [12, 14–20]. Inhibition of the Warburg effect has been shown to enhance the radiosensitivity of cancers [14, 21–23]. Similar results have also been found in laryngeal carcinoma [24–29].…”

Section: Introductionmentioning

confidence: 65%

“…Meng et al showed that silencing PKM2 expression by shRNA enhanced radiation-induced apoptosis and autophagy in non-small cell lung cancer cell lines and xenografts [21]. Pitroda et al identified new functions of STAT1, that its knockdown significantly induced radiosensitization of irradiated tumors, which indicated that STAT1 activation enhances the radioresistance of tumors [21]. Furthermore, mutation of tumor protein 53 (TP53) in head and neck squamous cell carcinoma (HNSCC) cells was found to be correlated with the Warburg effect.…”

Section: The Warburg Effect and Radioresistancementioning

confidence: 99%

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

Zhong

Zhou

2016

Oncotarget

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Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.

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“…A number of studies have demonstrated that increased aerobic tumor metabolism (glycolysis) is highly associated with the development of radioresistance by providing a chemically reduced milieu in the tumor microenvironment [11] and inhibition of glycolysis resulted in increased radiosensitivity [12]. The roles of glycolysis in CaP radioresistance are still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…As previous described, targeting autophagy was considered as an effective way of overcoming radioresistance [41]. Meng et al demonstrated that silencing PKM2 in the glycolysis pathway was shown to sensitize RT in NSCLC via inhibiting autophagy [12]. It was also reported that inhibition of autophagy by rapamycin and apoptosis inducer could effectively sensitize a lung cancer cell line to radiation [42].…”

Section: Discussionmentioning

confidence: 99%

Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy

et al. 2016

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Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry. One selected glycolysis marker, lactate dehydrogenase A (LDHA) was validated, and further investigated for its role in CaP radioresistance. We found that 378 proteins and 51 pathways were significantly differentially expressed between PC-3RR and PC-3 xenograft tumors, and that the glycolysis pathway is closely linked with CaP radioresistance. In addition, we also demonstrated that knock down of LDHA with siRNA or inhibition of LDHA activity with a LDHA specific inhibitor (FX-11), could sensitize PC-3RR cells to radiotherapy with reduced epithelial-mesenchymal transition, hypoxia, DNA repair ability and autophagy, as well as increased DNA double strand breaks and apoptosis. In summary, we identified a list of potential RR protein markers and important signaling pathways from a PC-3RR xenograft mouse model, and demonstrate that targeting LDHA combined with radiotherapy could increase radiosensitivity in RR CaP cells, suggesting that LDHA is an ideal therapeutic target to develop combination therapy for overcoming CaP radioresistance.

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Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo

Cited by 57 publications

References 56 publications

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

Proteomic identification of the lactate dehydrogenase A in a radioresistant prostate cancer xenograft mouse model for improving radiotherapy

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