Cathepsin B to Cysteine Proteinase Inhibitor Balance in Metastatic Cell Subpopulations Isolated from Murine Tumors

TY - JOUR

T1 - Cathepsin B to Cysteine Proteinase Inhibitor Balance in Metastatic Cell Subpopulations Isolated from Murine Tumors

AU - Rozhin, Jurij

AU - Gomez, Angel P.

AU - Ziegler, Grace H.

AU - Sloane, Bonnie F.

AU - Nelson, Kevin K.

AU - Chang, Young Sook

AU - Onoda, James M.

AU - Honn, Kenneth V.

AU - Fong, Dunne

PY - 1990/10/1

Y1 - 1990/10/1

N2 - Our laboratories have previously demonstrated that the malignancy of human and animal tumors is associated with increases in Cathepsin B activity, due in part to increases in Cathepsin B-specific RNA transcripts and in part to decreased regulation by the endogenous low molecular weight cysteine proteinase inhibitors (CPIs). In this study we have extended these observations to tumor cell subpopulations of B16 amela-notic melanoma (B16a) and Lewis lung carcinoma (3LL) isolated by centrifugal elutriation. B16a subpopulations exhibited a 10-fold differential in lung colonization potential, whereas 3LL subpopulations exhibited no differential. In the B16a subpopulations, Cathepsin B activities, total cellular and plasma membrane-associated, corresponded positively (4- and 10-fold increase, respectively) with their lung colonization potentials. CPI activities, total cellular and plasma membrane-associated, corresponded inversely (2- and 5-fold decrease, respectively) with the lung colonization potential of the B16a subpopulations. In the 3LL subpopulations, neither Cathepsin B nor CPI activities changed. In the plasma membrane fractions of all 3LL subpopulations the ratio of Cathepsin B activity to CPI activity was <1, whereas in the plasma membrane fractions of all B16a subpopulations the ratio was 1 or greater. In the plasma membrane fractions of the B16a subpopulations of higher lung colonization potential the ratios were 2.5 and 7, indicating that the levels of endogenous CPIs in these fractions may not be sufficient to regulate Cathepsin B activity. Cathepsin B mRNA levels were not increased in the B16a subpopulations expressing increased Cathepsin B activity. Thus increased Cathepsin B activity in these subpopulations was apparently due not to increased synthesis but to decreased regulation by the endogenous CPIs. These results suggest that membrane-associated Cathepsin B and CPIs may both play a role in the expression of the experimental metastatic phenotype.

AB - Our laboratories have previously demonstrated that the malignancy of human and animal tumors is associated with increases in Cathepsin B activity, due in part to increases in Cathepsin B-specific RNA transcripts and in part to decreased regulation by the endogenous low molecular weight cysteine proteinase inhibitors (CPIs). In this study we have extended these observations to tumor cell subpopulations of B16 amela-notic melanoma (B16a) and Lewis lung carcinoma (3LL) isolated by centrifugal elutriation. B16a subpopulations exhibited a 10-fold differential in lung colonization potential, whereas 3LL subpopulations exhibited no differential. In the B16a subpopulations, Cathepsin B activities, total cellular and plasma membrane-associated, corresponded positively (4- and 10-fold increase, respectively) with their lung colonization potentials. CPI activities, total cellular and plasma membrane-associated, corresponded inversely (2- and 5-fold decrease, respectively) with the lung colonization potential of the B16a subpopulations. In the 3LL subpopulations, neither Cathepsin B nor CPI activities changed. In the plasma membrane fractions of all 3LL subpopulations the ratio of Cathepsin B activity to CPI activity was <1, whereas in the plasma membrane fractions of all B16a subpopulations the ratio was 1 or greater. In the plasma membrane fractions of the B16a subpopulations of higher lung colonization potential the ratios were 2.5 and 7, indicating that the levels of endogenous CPIs in these fractions may not be sufficient to regulate Cathepsin B activity. Cathepsin B mRNA levels were not increased in the B16a subpopulations expressing increased Cathepsin B activity. Thus increased Cathepsin B activity in these subpopulations was apparently due not to increased synthesis but to decreased regulation by the endogenous CPIs. These results suggest that membrane-associated Cathepsin B and CPIs may both play a role in the expression of the experimental metastatic phenotype.

UR - http://www.scopus.com/inward/record.url?scp=0025005473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025005473&partnerID=8YFLogxK

M3 - Article

C2 - 2400991

SN - 0008-5472

VL - 50

SP - 6278

EP - 6284

JO - Cancer Research

JF - Cancer Research

IS - 19

ER -