探討Dovitinib藉由計畫性細胞死亡於人類乳癌細胞產生的抗腫瘤效果

Abstract

乳癌為女性最常罹患的癌症，其致死率為全球癌症排名的前五名。在台灣，乳癌更是女性好發癌症的榜首。根據歷年的癌症登記數據指出，我國女性的乳癌發生率亦有逐年增加的趨勢。因為乳癌對於健康的威脅如此重大，所以近年來乳癌已成為公共衛生上不可忽視的重要議題。Dovitinib 為一多重標的酪胺酸激酶接受器抑制劑，該藥物目前已針對許多癌症進行臨床試驗，惟對於乳癌尚未有完整的確效。有鑑於此，本研究旨在探討dovitinib對抗乳癌的效果與機制。在本研究中，dovitinib 能有效抑制所有受試乳癌細胞株 (MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-468, HCC1937, 和 SK-BR-3) 的細胞生長，且該細胞抑制效應隨著藥物濃度與作用時間的增加而遽增。此效應乃源於dovitinib 可透過調降STAT3的活化進而影響到下游的蛋白，包含Mcl-1及cyclin D1。外源性增加STAT3 的表現時可使乳癌細胞免於由dovitinib誘發的細胞凋亡，指出STAT3在dovitinib所引發的抗腫瘤效果之中扮演相當重要的角色。此外，給予SHP-1的活性抑制劑可以反轉dovitiniib造成的STAT3表現調降，顯示該藥透過活化SHP-1磷酸酶以調降STAT3的活性。此外，我們首先發現dovitinib 會藉由活化細胞自噬效應造成乳癌細胞的死亡。總結而言，dovitinib在乳癌細胞中，會藉由活化SHP-1磷酸脢來降低STAT3的磷酸化效應，進而誘發細胞凋亡與細胞自噬效應以促進乳癌細胞的死亡。

Breast cancer is the most common cancer in women and the mortality rate is in the rank of top fifth cancer. In Taiwan, breast cancer is also the top diagnosed cancer in women. Moreover, incidence rate of breast cancer keeps climbing high in the last 30 years. Therefore, breast cancer is the critical public health issue in recent years. Dovitinib is a novel multi-target receptor tyrosine kinase inhibitor, which has been enrolled in several clinical trials in different cancers. However, its anti-tumor efficacy has not been well determined in breast cancers. Our results demonstrated that dovitinib showed significant antitumor activity in human breast cancer cell lines with dose- and time-dependent manners. Down-regulation of phospho-STAT3 (p-STAT3) and its subsequent effectors Mcl-1 and cyclin D1 was responsible for this drug effect. Since ectopic expression of STAT3 rescued the breast cancer cells from cell apoptosis induced by dovitinib. Moreover, SHP-1 inhibitor reversed the downregulation of p-STAT3 induced by dovitinib, indicating that SHP-1 mediated the STAT3 inhibition effect of dovitinib. In addition to apoptosis, we found for the first time that dovitinib also activated autophagy to promote cell death in breast cancer cells. In conclusion, dovitinib induced both apoptosis and autophagy to block the growth of breast cancer cells through regulating the SHP-1depenent STAT3 inhibition.