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Effects of Insulin in Vivo and in Vitro on Amino Acid Transport into Cells from the R3230AC Mammary Adenocarcinoma and Their Relationship to Tumor Growth¹

Department of Biochemistry [P. J. H., R. H.] and The University of Rochester Cancer Center [R. H.], University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

The R3230AC mammary carcinoma grows faster in diabetic rats; tumor cells from diabetic rats demonstrate increased proline transport and incorporation into proteins compared to tumor cells obtained from intact rats. Tumor cells from insulin-treated diabetic rats showed a decreased rate of proline transport and a lower amount of proline incorporation, both of which were comparable to that in cells from intact rats. The effects of insulin in vivo were time and dose related. The rate of -aminoisobutyric acid entry, but not phenylalanine or leucine, was also higher in tumor cells from diabetic rats than in those from intact rats. Kinetic analysis of -aminoisobutyric acid uptake indicated that -aminoisobutyric acid was transported by two carriers. The increase in -aminoisobutyrate uptake in the absence of insulin was due to an increase (170%) in the V_max of the Na⁺-dependent component; no difference in K_m was observed. The Na⁺-independent component of -aminoisobutyric acid uptake was not significantly increased in cells from diabetic rats. No differences were observed in 3-O-methylglucose transport, ¹⁴CO₂ production from uniformly labeled glucose, or incorporation of labeled glucose into fatty acids for cells from intact or diabetic rats.

In contrast, insulin in vitro increased proline transport and its incorporation in cells from diabetic but not from intact rats. The response of cells from insulin-treated diabetic animals was blunted. These responses to insulin in vitro were shown to be dose related and occurred over the physiological range for insulin in vivo. Thus, the enhanced proline transport and incorporation seen in cells from diabetic rats may contribute to the enhanced tumor growth; administration of insulin in vivo reversed this effect on proline and reduced tumor growth. We suggest that these paradoxical effects of insulin in vivo versus those in vitro on proline transport may be due to the presence of other hormones in vivo, which modulate the effects of insulin.

¹ Supported by USPHS Grant CA 16660 and, in part, by Cancer Center Core Support CA Grant 5-P30-CA 11198-09, National Cancer Institute, NIH.

² Submitted in partial fulfillment of the requirements for the Ph.D. degree.

³ To whom requests for reprints should be addressed.

Received 12/16/77. Accepted 7/27/78.