Insulin-like Growth Factor I Induces Tumor Hexokinase RNA Expression in Cancer Cells

doi:10.1006/bbrc.1997.6797

Biochemical and Biophysical Research Communications

Volume 235, Issue 2, 18 June 1997, Pages 389-393

https://doi.org/10.1006/bbrc.1997.6797 Get rights and content

Abstract

Increased glycolysis is a characteristic of cancer cells. Though less efficient in energy production, it ensures continuous supply of energy and phosphometabolites for biosynthesis enabling metastatic and less vascularized cancer cells to proliferate even under hypoxic conditions. Since hexokinase is the first rate limiting enzyme in the glycolytic pathway, elevated levels of Type II like hexokinase in tumors are of great significance in this context. Under normal conditions insulin regulates expression of hexokinase Type II isoenzyme, which is predominantly expressed in muscle. On the other hand cancer cells overexpress insulin-like growth factors and their receptors which mimic many activities of insulin. This prompted us to examine a hypothesis that insulin-like growth factors may be responsible for overexpression of tumor hexokinase. Our experiments demonstrate that insulin-like growth factor I indeed induces hexokinase gene expression in a concentration and time dependent manner in two cancer cell lines we studied.

References (37)

E.F. Greiner et al.
J. Biol. Chem.
(1994)
S.K. Frank et al.
Arch. Biochem. Biophys.
(1986)
R.L. Printz et al.
J. Biol. Chem.
(1993)
R. Baserga
Cell
(1994)
P. Chomczynski et al.
Anal. Biochem.
(1987)
A.P. Thelen et al.
Arch. Biochem. Biophys.
(1991)
S.J. Pilkis
Biochym. Biophys. Acta.
(1970)
D.P. Kosow et al.
Biochem. Biophys. Res. Commun.
(1972)
K.K. Arora et al.
J. Biol. Chem.
(1988)
L. Rossetti et al.
J. Biol. Chem.
(1996)

P.Y. Chang et al.

J. Biol. Chem.

(1996)

D. Beitner-Johnson et al.

J. Biol. Chem.

(1995)

V.A. Blakesley et al.

Cytokine & Growth Factor Rev.

(1996)

O. Warburg

Science

(1956)

S. Weinhouse

Cancer Res.

(1972)

E.B. Goldgerg et al.

J. Biol. Chem.

(1965)

E. Eigenbrodt et al.

Biochemical and Molecular Aspects of Selected Cancers

(1994)

H.M. Katzen et al.

Proc. Natl. Acad. Sci. U.S.A.

(1965)

Cited by (15)

Targeted lactate dehydrogenase genes silencing in probiotic lactic acid bacteria: A possible paradigm shift in colorectal cancer treatment?
2023, Biomedicine and Pharmacotherapy
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
Lactic acidosis and colon cancer: Oncologic emergency?
2011, Clinical Colorectal Cancer
Citation Excerpt :
Tumor cells overexpress type II hexokinase, the enzyme responsible for catalyzing the first step of glycolysis.18 This enzyme is normally controlled by insulin, however, this control is disrupted by insulin-like growth factors (IGFs) and their receptors – also overexpressed by tumor cells – thereby allowing continued glycolysis and tumor proliferation.19 A series of patients with hematologic malignancies and lactic acidosis were found to have altered levels of IGFs and their binding proteins (IGFBP), which seemed to correlated with disease activity, supporting the theory that the IGF/IGFBP system plays a role in the development of malignancy associated lactic acidosis.20
We report the case of a 44-year-old woman who presented shortly after the diagnosis of metastatic colon cancer with profound lactic acidosis in the absence of tissue hypoperfusion or hypoxemia. Her acid-base disturbance was unresponsive to medical management but resolved after initiation of systemic chemotherapy. In addition to malignancy associated lactic acidosis, this case illustrates several other issues, including factors involved in choosing the initial chemotherapy regimen and sequencing subsequent therapies, and the role of carcinoembryonic antigen (CEA) in following response to treatment. It is important to report this case of a rare but serious complication of malignancy in order to increase recognition and understanding of this presentation.
The hepatitis E virus Orf3 protein protects cells from mitochondrial depolarization and death
2007, Journal of Biological Chemistry
The biology and pathogenesis of hepatitis E virus are poorly understood due to the lack of an in vitro culture or infection models. The viral Orf3 protein activates the cellular mitogen-activated protein kinase pathway and is likely to modulate the host cell environment for efficient viral replication. We screened for cellular genes whose transcription was differentially up-regulated in an Orf3-expressing stable cell line (ORF3/4). The gene for mitochondrial voltage-dependent anion channel (VDAC) was one such candidate. The up-regulation of VDAC in ORF3/4 cells was confirmed by Northern and Western blotting in various cell lines. Transfection of ORF3/4 cells with an ORF3-specific small interfering RNA led to a reduction in VDAC protein levels. VDAC is a critical mitochondrial outer membrane protein, and its overexpression results in apoptosis. Surprisingly, Orf3-expressing cells were protected against staurosporine-induced cell death by preservation of mitochondrial potential and membrane integrity. A small interfering RNA-mediated reduction in Orf3 and VDAC levels also made cells sensitive to staurosporine. Chemical cross-linking showed Orf3-expressing cells to contain higher levels of oligomeric VDAC. These cells also contained higher levels of hexokinase I that directly interacted with VDAC. This interaction is known to preserve mitochondrial potential and prevent cytochrome c release. We report here the first instance of a viral protein promoting cell survival through such a mechanism.
[<sup>18</sup>F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and inflammatory lesions of the lung
2005, Neoplasia
PURPOSE: The aim of this study was to evaluate the relationships among [¹⁸F]fluorodeoxyglucose ([¹⁸F]-FDG) uptake, Glut-1 and HK-II expressions, and grade of inflammation in resected lung lesions. MATERIALS AND METHODS: Sixty patients had undergone preoperative ¹⁸F-FDG-PET imaging and thoracotomy. For semi-quantitative analysis of ¹⁸F-FDG uptake, partial volume effect corrected maximum standardized uptake values (pSUVs) were calculated. Immunohistochemical staining was performed in resected specimens using anti-Glut-1, anti-HK-II, and anti-proliferative cellular nuclear antigen (PCNA) antibodies, and immunoreactivities were scored as G-, H-, and P-indexes on a five-point scale (0: 0%; 1:~20%, 2:~40%; 3:~60%; 4:~80%, and 5:~100% percentages of strongly immunoreactive cells). Grade of inflammation was also evaluated. RESULTS: The malignant lesions had higher pSUV and higher G- and H-indexes than nonmalignant lesions. pSUVs correlated with the G- (p < .001), H- (p < .01), and P-indexes (p < 0.01) in malignant lesions. In adenocarcinomas, cancers with lower differentiation showed higher expression of Glut-1 and HK-II than those with higher differentiation. A positive linear regression was observed between pSUVs and the grading of inflammation in nonmalignant lesions (p < 0.05). CONCLUSIONS: Our study indicates that ¹⁸F-FDG uptake in lung cancer correlates well with Glut-1, HK-II, and PCNA expression. For nonmalignant lesions, the presence of a higher inflammatory process correlated with ¹⁸F-FDG uptake.
Expression of hexokinase II and Glut-1 in untreated human breast cancer
2002, Nuclear Medicine and Biology
Expressions of HKII and Glut-1 were studied in untreated primary human breast cancers by immunohistochemistry. 79% of the breast cancers were HKII-positive and 61% were Glut-1-positive. Average positive malignant cell areas were 66 ± 41% for HKII and 29 ± 36% for Glut-1. HKII staining was cytoplasmic, suggesting mitochondrial localization with no variations in staining intensities. Glut-1 staining was heterogeneous, cytoplasmic and membranous and varied with histology and tumor stage. Cells expressing HKII did not always express Glut-1 and vice versa. Increased FDG-uptake appeared to be associated with increased Glut-1 expression (P = 0.021), but not with HKII expression (p = 0.6).
FDG uptake in breast cancer tissue appears to be associated with the extent of immunodetectable expression of Glut-1, but not that of HKII, and FDG uptake may differ between individual tumors depending on tumor stage and histology.
Growth condition-dependent synchronized changes in transcript levels of type II hexokinase and type 1 glucose transporter in tumor cells
2001, Biochimica et Biophysica Acta - Molecular Cell Research
Transcript levels of hexokinase (HK) isozymes and glucose transporter (GLUT) isoforms in RNA samples of AH130 cells obtained from dish cultures and ascites were evaluated in a quantitative manner. In AH130 cells cultured in dishes, HKI and HKII were expressed at a similar level, but HKIII and HKIV were not. GLUT1 and GLUT3 were also expressed, and messages of these two isoforms represented 27% and 71%, respectively, of the total GLUT messages. A faint signal of GLUT2 was also observed. On the contrary, in cells grown as ascites, the transcript of HKII was dominant, and its level was about 15-fold over that of dish-cultured AH130 cells. Transcript levels of GLUT1 and GLUT3 were 4.5- and 2-fold, respectively, higher than those in dish-cultured cells. Thus, GLUT1 was more susceptible to changes in culture conditions than GLUT3. Based on these results, we concluded that the change in growth conditions caused synchronized changes in the transcript levels of HKII and GLUT1 in AH130 cells. However, such marked changes in the transcript levels of HKII and GLUT1 were not observed when AH130 cells were cultured in dishes under a hypoxic condition, indicating that the observed changes were not solely attributable to the difference in oxygen concentration between the ascites and cell culture conditions. Accordingly, other factors such as growth factors may be responsible for this difference in levels of HKII and GLUT1 between the two growth conditions.

View all citing articles on Scopus

^☆: Abbreviations used: HK, hexokinaseGK, glucokinase; DMEM, Dulbecco's modified Eagle medium; IGF, insulin-like growth factor; BSA, bovine serum albumin; Glc-6-p, glucose 6-phosphate;

^☆☆: T. G. PretlowT. P. Iian Pretlow, Eds.

¹: To whom correspondance should be addressed at 301, Biochemistry Bldg., Michigan State University, East Lansing, MI 48824-1319. Fax: (517) 353-9334. E-mail: [email protected].

View full text

Regular ArticleInsulin-like Growth Factor I Induces Tumor Hexokinase RNA Expression in Cancer Cells☆,☆☆

Abstract

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Cell

Anal. Biochem.

Arch. Biochem. Biophys.

Biochym. Biophys. Acta.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cytokine & Growth Factor Rev.

Science

Cancer Res.

J. Biol. Chem.

Biochemical and Molecular Aspects of Selected Cancers

Proc. Natl. Acad. Sci. U.S.A.

Regular Article
Insulin-like Growth Factor I Induces Tumor Hexokinase RNA Expression in Cancer Cells☆,☆☆