<b>Conclusion:</b> HK1 and HK2 expression are redundant in tumors; either can provide sufficient aerobic glycolysis for tumor growth; despite a reduction in <sup>18</sup>F-FDG PET signal.
As the tumorHKII promoter plays a significant role in HKII overexpression, studies reported here were undertaken to identify both the major regions and transcription factors involved under tumor-like conditions.
Both HIF-1 alpha and HK II protein expressions were co-localized in the cancer cells near necrosis, and the intensity of HIF-1 alpha protein expression was significantly correlated with HK II mRNA expression in both tumors.
Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association.
Furthermore, high HK2 expression was significantly associated with some phenotypes of tumor aggressiveness, such as large tumor size (OR = 2.03 [1.10-3.74], P = 0.024), positive lymph node metastasis (OR = 2.05 [1.39-3.02], P < 0.001), advanced clinical stage (OR = 2.17 [1.21-3.89], P = 0.009) and high alpha fetoprotein level (OR = 1.47 [1.09-2.02] P = 0.013).
Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM.<b>Experimental Design:</b> We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature.
HK2 immunoreactivity was detected in 100 out of 195 (51%) colorectal carcinoma tissues, and the immunohistochemical HK2 status was significantly associated with tumor size, depth of invasion, liver metastasis and TNM stage in these cases.
HK2 knockdown increased the sensitivity of pancreatic cancer cell to GEM, the growth of xenograft tumor with HK2 knockdown was also further decreased with the GEM treatment compared with control in vivo.
Human laryngeal carcinoma Hep-2 cells were stably transfected with a plasmid expressing HK2 shRNA (pGenesil-1.1-HK2) and were compared to control cells with respect to the cell cycle, cell viability, apoptosis, and their ability to form xenograft tumors.
In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression.
In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten-/p53-deficiency-driven CRPC mouse model.
In HCC, hexokinase II positivity was associated with large tumor size (>4 cm) (<i>p</i> = 0.046), CAIX positivity with vascular invasion (<i>p</i> = 0.005), and MCT4 positivity with extrathyroidal extension (<i>p</i> = 0.030).
In vivo, our data demonstrated that interleukin-22 significantly promoted tumor growth along with elevated expression of c-Myc and hexokinase-2 in mice.
Increased lactate labeling in tumors correlated with c-Myc-driven expression of hexokinase 2, lactate dehydrogenase A, and the monocarboxylate transporters and was accompanied by increased radioresistance.
Increased mortality was associated with tumorHK2 expression (p = 0.003) as well as CKA expression (p = 0.03) with hazard ratios of 1.86 (95% confidence interval (CI) 1.23-2.83) and 1.59 (95% CI 1.04-2.41), respectively.
Interestingly, miR-143 expression was inversely associated with HK2 protein level but not mRNA level in human lung cancer samples. miR-143, down-regulated by mammalian target of rapamycin activation, reduces glucose metabolism and inhibits cancer cell proliferation and tumor formation through targeting HK2.