The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. Tyrosine kinase inhibitors (TKIs) are commonly used to treat CML; however, drug resistance of CML cells to TKIs has limited their clinical application. Shikonin, a traditional Chinese herb, has long been used to treat leukemia in China, but the roles and related molecular mechanisms of shikonin treatment in CML remain unclear. Here, we aimed to evaluate the effects of shikonin on the proliferation, apoptosis, and migration of K562 cells, a CML cell line. Firstly, K562 cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry with Annexin V-FITC/PI staining. Cell migration was measured by Transwell migration assay. In addition, western blot was performed to determine the proteins (PI3K, Bax, Bcl-2, cleaved caspase-3, PTEN, p-AKT, AKT, CXCR4, SDF-1, CD44) involved in the mechanism of action of shikonin. Finally, neutrophils from peripheral blood of CML patients were obtained, and cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry. Shikonin reduced the proliferation of K562 cells in a time- and dose-dependent manner and promoted the apoptosis of K562 cells. Moreover, shikonin increased the PTEN level and inactivated the PI3K/AKT signaling pathway, subsequently upregulating BAX in K562 cells. In addition, shikonin could block K562 cell migration via the CXCR4/SDF-1 axis. Finally, shikonin significantly inhibited the proliferation and promoted the apoptosis of neutrophils from CML patients. These results demonstrated that shikonin inhibits CML proliferation and migration and induces apoptosis by the PTEN/PI3K/AKT pathway, revealing the effects of shikonin therapy on CML.

Chen Y ，Wang T ，Du J ，Li Y ，Wang X ，Zhou Y ，Yu X ，Fan W ，Zhu Q ，Tong X ，Wang Y ... -  《-》

EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway.

Huang R ，Liu H ，Chen Y ，He Y ，Kang Q ，Tu S ，He Y ，Zhou X ，Wang L ，Yang J ，Wu A ，Li Y ... -  《-》

PTEN regulates BCRP/ABCG2 and the side population through the PI3K/Akt pathway in chronic myeloid leukemia.

Huang FF ，Zhang L ，Wu DS ，Yuan XY ，Yu YH ，Zhao XL ，Chen FP ，Zeng H ... -  《-》

TAL1 mediates imatinib-induced CML cell apoptosis via the PTEN/PI3K/AKT pathway.

Chronic myeloid leukemia (CML) is associated with chromosomal translocation t(9; 22), which results in formation of the BCR-ABL oncogene. CML is treated with tyrosine kinase inhibitors (TKIs), which target BCR-ABL, to eradicate BCR-ABL + cells. However, the TKI imatinib (IM) fails to eliminate quiescent leukemia stem cells (LSCs) in CML. In this study, we demonstrate that transcription factor TAL1 is down-regulated in CML LSCs by BCR-ABL, and IM triggers TAL1 mRNA expression. In addition, loss of TAL1 abrogates IM-induced CML cell apoptosis. RNA-seq analysis suggests that TAL1 expression may affect PI3K/AKT pathway. Moreover, depletion of TAL1 inhibits the expression of PTEN, which is a negative regulator of the PI3K/AKT pathway. Our results reveal an unexpected involvement of TAL1 in CML etiology and demonstrate that TAL1 may regulate PTEN expression and lead to inhibition of the PI3K/AKT pathway in the response of CML cells to TKI. These results implicate regulation of PTEN expression as a novel mechanism for the transcriptional regulatory networks of TAL1 in CML.

Wu Y ，Hu Y ，Yu X ，Zhang Y ，Huang X ，Chen S ，Li Y ，Zeng C ... -  《-》

Marsdenia tenacissimae extraction (MTE) inhibits the proliferation and induces the apoptosis of human acute T cell leukemia cells through inactivating PI3K/AKT/mTOR signaling pathway via PTEN enhancement.

Wang Y ，Chen B ，Wang Z ，Zhang W ，Hao K ，Chen Y ，Li K ，Wang T ，Xie Y ，Huang Z ，Tong X ... -  《Oncotarget》