Objective: Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition, not only aiding seeding and colonization, but also rendering the tumor cells generally chemoresistant. We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways, including PI3K-Akt, that protected the tumor cells from death; however, the extent of protection from blocking the pathway in its entirety was modest, because different isoforms may have alternately affected cell functioning. Here, we characterized Akt isoform expressions in primary and metastatic prostate cancers, as well as their individual contributions to chemoresistance. Methods: Akt isoforms and E-cadherin were manipulated with drugs, knocked down, and over expressed. Tumor cell killing was determined in vitro and in vivo. Overall survival was calculated from patient records and specimens. Results: Pan-Akt inhibition sensitized tumor cells to chemotherapy, and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive. Overexpression of Akt3 induced apoptosis. A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model, acting as chemosensitizers. In human specimens, we found Akt1 and Akt2 positively correlated, whereas Akt3 inversely correlated, with the overall survival of prostate cancer patients. Akt1high/Akt2high/Akt3low tumors had the worst outcomes. Conclusions: E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.

Bo Ma;Hanshuang Shao;Xia Jiang;Zhou Wang;Chuanyue(Cary)Wu;Diana Whaley;Alan Wells

Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,Cancer Institute,Xuzhou Medical University,Xuzhou 221002,China;Department of Pathology,University of Pittsburgh,Pittsburgh,PA 15261,USA;Pittsburgh VA Healthcare System,Pittsburgh,PA 15213,USA;Department of Biomedical Informatics;Department of Urology;Department of Pharmacology and Chemical Biology,University of Pittsburgh,Pittsburgh,PA 15261,USA;UPMC Hillman Cancer Center,Pittsburgh,PA 15232,USA

癌症生物学与医学（英文版）

[1]Bo Ma;Hanshuang Shao;Xia Jiang;Zhou Wang;Chuanyue(Cary)Wu;Diana Whaley;Alan Wells-.Akt isoforms differentially provide for chemoresistance in prostate cancer)[J].癌症生物学与医学（英文版）,2022(05):635-650

micrometastatic,reverting,chemoresistant,micrometastases,chemoresponsive,chemotherapies,chemosensitizers,Akt1high,Akt2high,Akt3low

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