The Study Of The Mechanism And Impact Of Autophagy On The Anti-multiple Myeloma (MM) Function Of Histone Deacetylase Inhibitors (HDACIs)

Multiple myeloma is a plasma cell originated hematologic malignancy that accounts for 1%of human cancers. In spite of the great progress achieved so far in the treatment strategies of high dosage chemotherapy with autologous hematopoietic stem cell transplantation and immunomodulators and the studies of proteasome inhibitors etc., resistance to drug treatment and disease relapse remains a great difficulty. Therefore, development of novel treatment strategies targeting MM is an urgent issue to be solved in a clinical context.Histone deacetylase inhibitors (HDACIs) is a novel anti-tumor drug targeted at histone acetylation modification. It exerts its anti-tumor effect mainly through up-regulation of tumor suppressor genes, inducing selective apoptosis of tumor cells, increasing the level of histone acetylation and thus improving expression level of p21 etc. The second generation of HDACIs-suberoylanilide hydroxamic acid, SAHA has been used for clinical treatment of relapsed or refractory cutaneous T cell lymphoma. Recent pre clinical research results shows that, SAHA also has a good anti-tumor effect on MM. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma has been conducted demonstrating modest single-agent activity.Autophagy is a basic metabolic process which includes the degradation of non-essential or abnormal proteins mediated by lysosomes. The autophagic process refers to an important process of bilayer membrane shed from the rough endoplasmic reticulum non ribosomal attached area parceling some damaged proteins or organelles and other ingredients forming autophagosome and later autolysosome by its fusion with lysosomes to degrade its contents, by such achieving removal or degradation of its damaged or excess biological macromolecules to maintain metabolic balance and homeostasis. Autophagy includes macroautophagy, chaperone-mediated autophagy and microautophagy.Recent studies reported that change in the activity of macroautophagy is closely related to the occurrence and development of MM and that the change in the state of autophagy activity in cells can influence the anti-tumor effect of anti-tumor drugs. Some scholar reported that regulating autophagy activity can change the anti-glioblastoma effect of S AHA. Current study also found that, the key rate limiting protein Lysosome-associated membrane protein 2 A, LAMP2A in the chaperone-mediated autophagy. CMA pathway is highly expressed in breast cancer or lung cancer, and the silencing or overexpression of LAMP2A can inhibit or promote the growth of breast cancer or lung cancer cells, suggesting that CMA may also play an important role in the occurrence and development of MM, thus regulation of CMA activity may also affect the the anti MM effect of SAHA. However, there has been no reports in a MM cell context concerning SAHA’s role in autophagy regulation and how the changed autophagy activity influences SAHA’s anti-MM ability.In this study, based on observation of SAHA’s effect on autophagy and its mechanism in MM cells, through autophagy activity regulation, we discussed the influence of regulating autophagy activity on the anti MM effect of SAHA and its possible molecular mechanism.We found that in multiple myeloma cells SAHA can induce autophagy by suppressing AKT/mTORCl pathway. Combining treatment of SAHA with an autophagy inhibitor 3-MA reduced the level of autophagy and enhanced the antiproliferative activity of SAHA, leading to increased cell apoptosis. We also managed to obtain LAMP2A low expression stable cell line with the constructed human LAMP2A-shRNA lentiviral vector. We found that down regulation of LAMP2A expression significantly inhibited MM.1S cell proliferation and enhanced the anti-tumor activity of SAHA. Interestingly, down regulation of LAMP2A expression also inhibited MM.1S cell lactic acid secretion. This study is expected to improve the understanding of the relationship between autophagy and MM, a new idea for the MM study, and possibly new targets and useful clues for clinical diagnosis and treatment of MM.