Presence of activated ras correlates with increased cysteine proteinase activities in human colorectal carcinomas

Kim, Kwonseop; Cai, Jinguo; Shuja, Sania; Kuo, Tom K.; Murnane, Mary Jo

doi:10.1002/(sici)1097-0215(19980821)79:4<324::aid-ijc4>3.0.co;2-x

Cited by 36 publications

(14 citation statements)

References 24 publications

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“…Variations in cathepsin H expression with cancer site may reflect the different genetic pathways described for colorectal cancers in left versus right colon. Correlations between these molecular markers and cathepsin B and L activities in colorectal cancers have already been reported (Iacobuzio-Donahue et al, 1996;Kim et al, 1998). A comparison of our cathepsin H activity data for clinical stage and site confirmed that both variables could be related to elevated Figure 7 Cathepsin H immunohistochemical staining in colorectal cancer.…”

Section: Discussionsupporting

confidence: 83%

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Shuja

Cai

et al. 2000

Br J Cancer

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SummaryOur analyses of cathepsin H activity levels and protein forms in human colorectal cancers compared to matched control mucosa support the concept that altered proteinase expression patterns may reflect both cancer stage and site. Cathepsin H-specific activity was significantly increased in colorectal cancers compared to control mucosa (P = 0.003; n = 77). Highest specific activities and cancer/normal ratios (C/N) for activity were measured in Dukes' B and C stage carcinomas, cancers involved in local spread and invasion to lymph nodes. In contrast, cathepsin B and L activities analysed in the same paired extracts had been shown to be most frequently elevated in earlier stage carcinomas (Dukes' A and B), confirming that cathepsin H demonstrates a distinct pattern of expression during colorectal cancer progression. Although cathepsin H activities were most commonly elevated in Dukes' C cancers at all colon sites, both specific activity and C/N ratios were significantly higher for cancers of the left colon compared to other colon locations. A subset of 43 paired extracts analysed on Western blots also revealed consistent changes in cathepsin H protein forms in cancers. Normal mucosa typically showed a strong protein doublet at 31 and 29 kDa while cancers demonstrated decreased expression or total loss of the 31 kDa protein (90% of cases), equal or increased expression of the 29-kDa protein (67% of cases) and the new appearance or up-regulation of a cathepsin H band at 22 kDa (78% of cases). C/N ratios for cathepsin H enzyme activity correlated significantly with C/N ratios for the 29 kDa mature single-chain protein form (P < 0.001), with increased activity most commonly associated with elevated expression of 29-kDa cathepsin H but also with up-regulation of the 22-kDa band, suggesting a shift to more fully processed, mature active cathepsin H protein forms in cancers. Changes in cathepsin H expression were also detected by immunohistochemistry as elevated cathepsin H staining in tumour epithelial cells.

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Section: Discussionsupporting

confidence: 83%

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Shuja

Cai

et al. 2000

Br J Cancer

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“…The mechanism by which Ras activation increases reovirus growth has been suggested to involve inactivation of the interferoninduced eIF2␣ kinase PKR (64). Interestingly, it has been demonstrated that Ras activation can result in increased expression of various proteases, including cathepsin L (17,18,44). Since reovirus infection can be mediated by cathepsin L, higher levels of this protease could make Ras-activated cells more permissive to infection.…”

Section: Discussionmentioning

confidence: 99%

Addition of Exogenous Protease Facilitates Reovirus Infection in Many Restrictive Cells

Golden

Linke

Schmechel

et al. 2002

J Virol

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Virion uncoating is a critical step in the life cycle of mammalian orthoreoviruses. In cell culture, and probably in extraintestinal tissues in vivo, reovirus virions undergo partial proteolysis within endosomal or/or lysosomal compartments. This process converts the virion into a form referred to as an intermediate subvirion particle (ISVP). In natural enteric reovirus infections, proteolytic uncoating takes place extracellularly within the intestinal lumen. The resultant proteolyzed particles, unlike intact virions, have the capacity to penetrate cell membranes and thereby gain access to cytoplasmic components required for viral gene expression. We hypothesized that the capacity of reovirus outer capsid proteins to be proteolyzed is a determinant of cellular host range. To investigate this hypothesis, we asked if the addition of protease to cell culture medium would expand the range of cultured mammalian cell lines that can be productively infected by reoviruses. We identified many transformed and nontransformed cell lines, as well as primary cells, that restrict viral infection. In several of these restrictive cells, virion uncoating is inefficient or blocked. Addition of proteases to the cell culture medium generates ISVP-like particles and promotes viral growth in nearly all cell lines tested. Interestingly, we found that some cell lines that restrict reovirus uncoating still express mature cathepsin L, a lysosomal protease required for virion disassembly in murine L929 cells. This finding suggests that factors in addition to cathepsin L are required for efficient intracellular proteolysis of reovirus virions. Our results demonstrate that virion uncoating is a critical determinant of reovirus cellular host range and that many cells which otherwise support productive reovirus infection cannot efficiently mediate this essential early step in the virus life cycle.Mammalian reoviruses (reoviruses) are prototypic members of the Reoviridae family, which includes the pathogenic rotaviruses, coltiviruses, and orbiviruses. Whereas reovirus causes infections that are generally asymptomatic in humans, it can induce respiratory, enteric, and nervous system diseases in animal models (reviewed in reference 67). Reovirus virions comprise a multilayered protein capsid that surrounds a segmented, double-stranded RNA genome (reviewed in reference 51). The outermost capsid layer consists of protein 3. The presence of 3 imparts environmental stability to the virion (54) but also appears to negatively regulate critical virion functions such as membrane penetration. The ability of reovirus to establish a productive infection requires proteolysis of the outer capsid (13,62,65). More recent data point toward 3 as the critical target for degradation (19,20).The first step in reovirus infection is attachment to cellular receptors through interactions with the viral receptor protein 1 (46, 75). Following attachment, virions are internalized by receptor-mediated endocytosis and delivered to endosomal compartments (12,13,65). In cell c...

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“…Matrix protease cathepsin L is an important marker for invasive tumors (Cuvier et al, 1997;Kim et al, 1998). Similarly, TGFb has been shown to be important in inducing the invasive behavior in several tumor cells including A549 (Hojo et al, 1999;Fujimoto et al, 2001;Hata, 2001).…”

Section: Mitochondrial Stress-induced Changes In the Cytoplasmic And mentioning

confidence: 99%

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

Amuthan

Biswas

Ananadatheerthavarada

et al. 2002

Oncogene

231

271

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We have investigated mechanisms of mitochondrial stressinduced phenotypic changes and cell invasion in tumorigenic but poorly invasive human pulmonary carcinoma A549 cells that were partly depleted of mitochondrial DNA (mtDNA). Depletion of mtDNA (genetic stress) caused a markedly lower electron transport-coupled ATP synthesis, loss of mitochondrial membrane potential, elevation of steady state [Ca 2+ ] c , and notably induction of both glycolysis and gluconeogenic pathway enzymes. Markers of tumor invasion, cathepsin L and TGFb1, were overexpressed; calcium-dependent MAP kinases (ERK1 and ERK2) and calcineurin were activated. The levels of anti-apoptotic proteins Bcl2 and Bcl-X L were increased, and the cellular levels of pro-apoptotic proteins Bid and Bax were reduced. Both mtDNA-depleted cells (genetic stress) and control cells treated with carbonyl cyanide m-chlorophenylhydrazone (metabolic stress) exhibited higher invasive behavior than control cells in a Matrigel basement membrane matrix assay system. MtDNA-depleted cells stably expressing anti-sense cathepsin L RNA, TGFb1 RNA, or treated with specific inhibitors showed reduced invasion. Reverted cells with 80% of control cell mtDNA exhibited marker protein levels, cell morphology and invasive property closer to control cells. Our results suggest that the mitochondriato-nucleus signaling pathway operating through increased [Ca 2+ ] c plays an important role in cancer progression and metastasis. Oncogene (2002Oncogene ( ) 21, 7839 -7849. doi:10.1038 Keywords: mitochondria; calcium signaling; cathepsin L; TGFb; tumor invasion; MAP kinases IntroductionThe role of mitochondria in carcinogenesis was initially suggested by Warburg et al. (1926;Warburg, 1956), based on the observation that number of experimentally induced rodent tumors exhibit reduced respiration-coupled oxidative metabolism and increased glycolysis. Since then, altered mitochondrial morphology, as well as changes in mitochondrial enzyme patterns and membrane transport systems, have been described in several tumor types (Zafar et al., 1982). Cell fusion studies (Jonasson et al., 1977;Howell and Sager, 1978;Giguere and Morais, 1981) also suggest that unknown cytoplasmic elements may play roles in carcinogenesis. Fusion between normal cytoplasm and karyoplasts from malignant phenotypes resulted in the ablation of tumorigenicity (Israel and Schaeffer, 1987) and conversely, the cytoplasm of the malignant phenotype could transfer the malignancy to the karyoplasts from normal cells (Israel and Schaeffer, 1988). Studies using mitochondrial DNA (mtDNA)-depleted tumor cells to evaluate the role of mtDNA, and thus mitochondrial function in tumorigenicity have yielded mixed results (Giguere and Morais, 1981;Morais et al., 1994;Cavalli et al., 1997;Cavalli and Liang, 1998;Hofhaus and Gattermann, 1999). Cavalli et al. (1997) found diminished tumor formation by glioblastoma cells following depletion of mtDNA (r 0 cells) with ethidium bromide treatment, while Morais et al. (1994) found increased capacity to p...

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Presence of activated ras correlates with increased cysteine proteinase activities in human colorectal carcinomas

Cited by 36 publications

References 24 publications

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Addition of Exogenous Protease Facilitates Reovirus Infection in Many Restrictive Cells

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

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