Autocrine Artemin And Prolactin In The Regulation Of Therapeutc Resistance Of Anti-cancer Drugs

For human cancer, surgery remains the first selection. Adding with adjunctive therapy methods, such as radiotherapy, chemotherapy and gene targeted drugs may have a good therapeutic effect. However, primary or acquired resistance to anti-cancer drugs remains a problem. In our study, we found neurotrophic factor Artemin promoted Herceptin resistance in mammary carcinoma and autocrine prolactin promoted resistance to doxorubicin and paclitaxel in endometrial carcinoma.Previous studies have demonstrated that ARTEMIN (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein we report that ARTN mediates acquired resistance to Trastuzumab in HER2positive mammary carcinoma cells. Ligands which increase HER2activity increased ARTN expression in HER2positive mammary carcinoma cells, whereas Trastuzumab inhibited ARTN expression.Forced expression of ARTN decreased the sensitivity of HER2positive mammary carcinoma cells to Trastuzumab both in in vitro and in vivo. Conversely siRNA mediated depletion of ARTN enhanced Trastuzumab efficacy. Cells with acquired resistance to Trastuzumab exhibited increased ARTN expression. The depletion of which restored Trastuzumab sensitivity. The Trastuzumab resistant cells conferred a greater CSC population with enhanced mammospheric growth by an increased BCL-2expression. ARTN mediated increased CSC population were abrogated upon functional inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to Trastuzumab in HER2positive mammary carcinoma cells.Forced expression of prolactin (hPRL) in human endometrial carcinoma (EC) cells generated a model of autocrine hPRL in EC cells. hPRL in EC cells dramatically increased cell proliferation and cell viability. Accordingly, forced expression of hPRL significantly enhanced anchorage-independent growth, migration and invasiveness of EC cells. Moreover, in xenograft models forced expression of hPRL increased tumor size, produced highly proliferative, poorly differentiated tumors, and promoted local invasion and metastatic colonization. Meanwhile, forced expression of hPRL decreased sensitivity of EC cells to chemotherapeutics including doxorubicin and paclitaxel both in vitro and in vivo. CD24played an important role and was regulated by hPRL. Depletion of CD24in EC cells abrogated hPRL-stimulated resistance to doxorubicin and paclitaxel. Small interfering RNA-mediated depletion of hPRL significantly reduced oncogenicity, invasion and enhanced sensitivity to chemotherapeutics of EC cells. Therefore, inhibition of hPRL may be considered as a potential therapeutic strategy to retard progression of EC and an adjuvant therapeutic approach to improve the response of EC to specific chemotherapeutic agents.