P38调控内质网应激诱导胃癌细胞对化疗药物产生耐药的分子机制

Endoplasmic reticulum stress (ER stress) could trigger a series of cyto-protective responses, which could render the resistance of tumor cells to the chemotherapy. Our priliminary data showed that ER stress could induce the chemoresistance via activation of P38 mitogen-activated protein kinase (MAPK) pathway.ER stress could also enhance the expression of MDR1 gene. However, the relationship between MDR1 gene expression and P38 activation is far from being elucidated. As a downstream signal molecule, AP-1 could bind to the promoter of MDR1 gene and regulate its expression. We speculate that ER stress-induced chemoresistance may via enhancing the transcription activity of AP-1 through P38 pathway to increase MDR1 gene expression,which will be explored as follows: 1.It will be tested that whether ER stress could enhance the transcription activity of AP-1, whether inhibition of AP-1 activity could downregulate MDR1 gene expression and chemosensitivity of gastric cancer cells under ER stress. 2. It will be explored that whether P38 inhibition could downregulate AP-1 transcription activity and MDR1 gene expression. 3. It will be investigated that whether AP-1 inhibition could increase the chemosensitivity in P38 overexpression gastric cancer cells under ER stress, which could confirm the role of AP-1 in P38 regulated- and ER stress induced-chemoresistance in gastric cancer cells and provide convincible evidence to address the molecular mechanism of P38 involved-chemoresistance induced by ER stress.

内质网应激反应是细胞逃避损伤的一种自我保护反应，可诱导肿瘤细胞耐药。前期研究显示内质网应激可激活P38诱导胃癌细胞耐药，且可增强多药耐药基因MDR1的表达。但P38如何调控内质网应激诱导胃癌细胞耐药及其与MDR1的关系不明。AP-1为P38下游分子，可与MDR-1启动子结合。推断内质网应激可能经P38调控AP-1活性，提高MDR1基因表达，诱导胃癌细胞耐药。本课题拟就此展开研究：1.明确内质网应激能否增强AP-1转录活性；内质网应激状态下抑制AP-1活性对MDR1编码产物P-gp表达量及胃癌细胞化疗敏感性的影响。2. 内质网应激状态下抑制P38活性能否下调AP-1活性及P-gp表达量。3.内质网应激状态下抑制AP-1活性能否提高P38过表达胃癌细胞的化疗敏感性，以明确AP-1在P38调控内质网应激诱导胃癌细胞耐药中的作用，阐明P38参与内质网应激诱导胃癌细胞耐药的分子机制。

胃癌是常见恶性肿瘤, 其死亡率高居我国恶性肿瘤死亡率之首。肿瘤细胞的多药耐药及其转移是导致患者死亡的主要原因。本研究发现内质网应激可通过激活P38通路诱导胃癌细胞对化疗药物产生耐药；内质网应激可增强AP1的转录活性及P－gp的蛋白表达；内质网应激状态下，抑制AP－1活性，可下调P－gp的表达，提高胃癌细胞对化疗药物的敏感性；内质网应激状态下，过表达P38可增强AP1的转录活性及胃癌细胞对化疗药物的耐药。提示内质网应激可通过激活P38通路，上调AP－1转录活性，提高MDR－1的基因表达，诱导胃癌细胞对化疗药物产生耐药。同时，本课题组发现内质网应激可促进胃癌细胞的迁移与侵袭；而内质网应激相关蛋白calreticuliln则参与调控肝癌的增殖与转移,提示内质网应激可能在调控胃癌及肝癌转移方面发挥重要作用。因此，内质网应激反应可能参与调控不同肿瘤细胞的多种生物学行为。