Rhodospirillum rubruml-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition

• Published in: Biochemical and biophysical research communications Vol. 492; no. 2; pp. 282 - 288
• Main Authors: Zhdanov, Dmitry D., Pokrovsky, Vadim S., Pokrovskaya, Marina V., Alexandrova, Svetlana S., Eldarov, Mikhail A., Grishin, Dmitry V., Basharov, Marsel M., Gladilina, Yulia A., Podobed, Olga V., Sokolov, Nikolai N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.10.2017
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Antitumor activity; Asparaginase - genetics; Asparaginase - therapeutic use; Cell Line, Tumor; Down-Regulation - drug effects; Enzyme Inhibitors - therapeutic use; Female; hTERT; Humans; Mice, Inbred BALB C; Mice, Nude; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Point Mutation; Rhodospirillum - enzymology; Rhodospirillum - genetics; Rhodospirillum rubrum l-asparaginase; Telomerase; Telomerase - genetics; Telomere length; Telomere Shortening - drug effects; RrA; RT-PCR; TGI; Antitumor activity; Rhodospirillum rubrum l-asparaginase; hTERT; Telomere length; MTT; Telomerase; IU/ml; MTV
• DOI: 10.1016/j.bbrc.2017.08.078
• ISSN: 0006-291X

Rhodospirillum rubruml-asparaginase mutant RrA E149R, V150P, F151T (RrA) was previously identified to down-regulate telomerase activity along with catalyzing the hydrolysis of l-asparagine. The aim of this study was to define the effect of prolonged RrA exposure on telomerase activity, maintenance of telomeres and proliferation of cancer cells in vitro and in vivo. RrA could inhibit telomerase activity in SCOV-3, SkBr-3 and A549 human cancer cell lines due to its ability to down-regulate the expression of telomerase catalytic subunit hTERT. Telomerase activity in treated cells did not exceeded 29.63 ± 12.3% of control cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell death in vitro. Using real time PCR we showed that length of telomeres in SCOV-3 cells has been gradually decreasing from 10105 ± 2530 b.p. to 1233 ± 636 b.p. after 35 days of cultivation. RrA treatment of xenograft models in vivo showed slight inhibition of tumor growth accompanied with 49.5–53.3% of decrease in hTERT expression in the all tumors. However down-regulation of hTERT expression, inhibition of telomerase activity and the loss of telomeres was significant in response to RrA administration in xenograft models. These results should facilitate further investigations of RrA as a potent therapeutic protein. •R. rubruml-asparaginase mutant E149R, V150P, F151T (RrA) down-regulates telomerase.•Telomerase activity in treated cancer cells does not exceed 30% of control cells.•Continuous RrA exposure results in shortening of telomeres followed by cell death.•RrA reduces hTERT expression by 50% in SCOV-3, SkBr-3 and A549 xenografts.