新型热疗通过PI3K/Akt/mTOR通路介导细胞自噬逆转结肠癌MDR的效果及机制研究

Multidrug resistance (MDR) is an important factor in the failure of colon cancer chemotherapy, hyperthermia plays an important role in the reversal of MDR. Autophagy has an important role to protect and maintain tumor cells survival and the role of autophagy in reversal of tumor MDR is a hot spot. PI3K/Akt/mTOR is one of the most important signal pathway to regulate autophagy. Our preliminary studies confirmed that hyperthermia could enhance the chemosensitivity of colon cancer. Recent studies have also confirmed that hyperthermia could reverse MDR of colon cancer by PI3K/Akt/mTOR signal pathway. However, whether MDR reversed by hyperthermia has correlation with autophagy regulated by PI3K/Akt/mTOR signal pathway is unclear. Therefore, we designed the research project as follows:first, hyperthermia combined with autophagy inhibitors can reverse MDR of colon cancer more effectively; second, autophagy inhibition plays an important role in hyperthermia reversing MDR of colon cancer by detecting LC3-Ⅱ, Beclin-1, etc; third, to elucidate the mechanism between autophagy regulated by PI3K/Akt/mTOR signal pathway and MDR of colon cancer reversed by hyperthermia. This research project aims to explore a new method of reversing MDR of colon cancer and provide the theoretical basis for the combination of hyperthermia and autophagy inhibitors to reverse MDR.

多药耐药（MDR）是结肠癌化疗失败的重要因素，热疗在逆转MDR中有重要作用。细胞自噬具有保护和维持恶性肿瘤细胞生存的重要功能，它在恶性肿瘤MDR中的作用是当今肿瘤学研究的热点，而PI3K/Akt/mTOR是调控自噬的重要信号通路之一。我们前期研究证实热疗能够增强结肠癌化疗的敏感性，最近研究也证实热疗能够通过PI3K/Akt/mTOR信号通路逆转结肠癌化疗的MDR。然而，热疗逆转MDR的作用是否与PI3K/Akt/mTOR介导的自噬有关，机制尚不清楚。本课题拟设计下列内容：①热疗和自噬抑制剂联合应用能更有效逆转MDR；②通过检测LC3-Ⅱ、Beclin-1等验证自噬抑制在热疗逆转结肠癌MDR中起重要作用；③阐明PI3K/Akt/mTOR信号通路调控的自噬对热疗逆转结肠癌MDR的可能机制。本课题旨在探索一种新的逆转结肠癌MDR的方法及其机制，为热疗和自噬抑制剂联合应用逆转MDR提供理论基础。

多药耐药（MDR）是结肠癌化疗失败的重要因素，热疗在逆转MDR中有重要作用。细胞自噬具有保护和维持恶性肿瘤细胞生存的重要功能，它在恶性肿瘤MDR中的作用是当今肿瘤学研究的热点，而PI3K/Akt/mTOR是调控自噬的重要信号通路之一。我们前期研究证实热疗能够增强结肠癌化疗的敏感性，最近研究也证实热疗能够通过PI3K/Akt/mTOR信号通路逆转结肠癌化疗的MDR。然而，热疗逆转MDR的作用是否与PI3K/Akt/mTOR介导的自噬有关，机制尚不清楚。本课题通过研究发现：①热疗和自噬抑制剂联合应用能更有效逆转MDR；②通过检测LC3-Ⅱ、Beclin-1等验证自噬抑制在热疗逆转结肠癌MDR中起重要作用；③阐明PI3K/Akt/mTOR信号通路对热疗逆转结肠癌MDR的可能机制。本课题探索了一种新的逆转结肠癌MDR的方法及其机制，为热疗和自噬抑制剂联合应用逆转MDR提供了理论基础。