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Alterations in the Activity and Isozymic Profile of Human Phosphofructokinase during Malignant Transformation in Vivo and in Vitro: Transformation- and Progression-linked Discriminants of Malignancy¹

Departments of Pediatrics [S. V.], and Internal Medicine [J. P. H.], and Pathology [D. M. K.], Columbia University, College of Physicians and Surgeons, New York, New York 10032, and Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California [S. V.]

6-Phosphofructokinase (PFK) plays a central role in the regulation of glycolysis in both normal and neoplastic cells. Since PFK also mediates the Pasteur effect, it coordinates the two modes of energy production in most cell systems, i.e., glycolysis and respiration. The energy production in the cancer cell is characterized by a predominance of aerobic glycolysis (the Warburg effect) and a diminution or lack of the Pasteur effect.

Previous studies from this laboratory have demonstrated that PFK in humans and in the rat exists in multiple tetrameric isozymic forms consisting of three unique subunits under separate genetic controls, M, L, and P types. These isozymes are distinguishable from one another by ion-exchange chromatography and subunit-specific antibodies. Various organs exhibit unique isozyme distribution patterns which essentially reflect the preferred mode of carbohydrate metabolism utilized, i.e., glycolysis or gluconeogenesis or both.

In order to investigate whether the high aerobic glycolysis of the cancer cell can be explained on the basis of a lack of the regulatory function of PFK due to an altered isozyme distribution pattern, we compared the activity and isozymic profile of the enzyme from malignant cells of human leukemias, lymphomas, virus-transformed cell lines, and established malignant cell lines of lymphoid, myeloid, erythroid, and fibroblastic origin and their normal counterparts. The myeloid and erythroid cell lines were also investigated after in vitro differentiation induced by dimethyl sulfoxide, sodium butyrate, hemin, etc. Our results show that, as is the case with hexokinase and pyruvate kinase, the other two rate-limiting enzymes of glycolysis, PFK shows both quantitative increases and isozymic alterations secondary to altered gene expression during neoplastic transformation, both in vivo and in vitro. In contradistinction to the isozymic alteration in hexokinase and pyruvate kinase, where highly regulated liver-type isozymes decrease or disappear and are replaced by the nonregulated ones, in the case of PFK, the highly regulated liver-type isozyme not only persists but actually increases, followed by an increase in the platelet-type isozyme. These isozymic alterations closely parallel the quantitative increases in total PFK activity, which in turn is closely related to the rate of replication of cancer cells and hence an increase in metabolism. Thus, human PFK is both a transformation- and a progression-linked discriminant of malignancy (For definitions of these terms, see Weber et al., N. Engl. J. Med., 296: 486–493, 1977.). These data, taken together with those reported in the literature, suggest that altered regulatory properties of tumor PFKs secondary to isozymic alteration may be partly responsible for the Warburg effect and a weakening of the Pasteur effect in the cancer cell.

¹ This work was supported in part by Grants AM 33445 and EY 03357 from the NIH and by grants from the Cancer Research Institute and the New York State AIDS Institute. This is Publication 3760-BCR from the Research Institute of Scripps Clinic and Research Foundation.

² Recipient of a Research Career Development Award (K04 AM01260) from the NIH. To whom requests for reprints should be addressed, at Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, BCR-7, La Jolla, CA 92037.

³ Present address: New York University School of Medicine, Department of Pathology, 550 First Avenue, New York, NY 10016.

Received 12/ 3/84. Revised 4/ 9/85. Accepted 4/11/85.

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