osi-027 and Colonic-Neoplasms

Colon cancer is a gastrointestinal malignancy that is one of the leading causes of tumor-associated deaths. It has been reported that the mammalian target of rapamycin (mTOR) can lead to the progression of colon cancer. However, the mechanism by which mTOR inhibitor (OSI-027) mediates the tumorigenesis of colon cancer remains largely unknown. Cell function of colon cancer was investigated by cell counting kit-8 flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, quantitative real-time polymerase chain reaction and Western blot were used to investigate the mechanism underlying the function of OSI-027 in colon cancer. OSI-027 dose-dependently reduced colon cancer cell viability by inducing cell apoptosis. In addition, OSI-027 induced the apoptosis of colon cancer cells via upregulation of PUMA. OSI-027 promoted the expression of PUMA by activation of forkhead box protein O3a (FOXO3a), and c-Myc knockdown partially increased FOXO3a and PUMA levels. Moreover, OSI-027 attenuated the tumor growth of colon cancer through the mediation of the mTOR/c-Myc/FOXO3a axis. OSI-027 attenuates colon cancer progression through the mediation of the c-Myc/FOXO3a/PUMA axis. Thereby, this study might shed new insights on exploring the strategies against colon cancer.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic; Colonic Neoplasms; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Imidazoles; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Triazines

Colorectal cancer is the third most frequently diagnosed malignancies among both men and women, which has an increased mortality but a poor prognosis. Targeting mTOR becomes an effective approach that shows promising antitumor activities in various cancers including colonic carcinoma. However, the potential mechanism against colon cancer remains incompletely understood. Here, we demonstrated that the anti-cancer effect of AZD8055 and OSI-027 is at least in part modulated by the gradual process of apoptosis initiation, progressing from mTOR suppression, 4EBP1 dephosphorylation, or EZH2 suppression, thereby leading to PUMA-dependent apoptosis via the intrinsic mitochondrial pathway. Furthermore, AZD8055 inhibited colorectal cancer tumor growth in mice significantly. PUMA deletion caused resistance of dual mTOR inhibitors, suggesting PUMA mediated carcinogenesis in vitro and in vivo. Collectively, these findings established a vital status of PUMA in driving the antineoplastic efficacy of targeting mTOR by AZD8055 and OSI-027 and offered the rationales for the current clinical assessment.

Topics: Animals; Apoptosis Regulatory Proteins; Colonic Neoplasms; DNA-Binding Proteins; Female; HCT116 Cells; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Morpholines; Proto-Oncogene Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors; Triazines; Xenograft Model Antitumor Assays