Department of Dermatology, No.1 Hospital of China Medical University and Key Laboratory of Immunodermatology, Ministry of Health and Ministry of Education, Shenyang 110001, China.
Key Laboratory of Medical Cell Biology, China Medical University, Shenyang, 110122, China.
Int J Biol Sci. 2019 Jan 1;15(3):568-578. doi: 10.7150/ijbs.29759. eCollection 2019.
Hyperthermia has been clinically utilized as an adjuvant therapy in the treatment of cervical carcinoma. However, thermotolerance induced by heme oxygenase-1 (HO-1), a stress-inducible cytoprotective protein, limits the efficacy of hyperthermic therapy, for which the exact mechanism remains unknown. In the present study, we found that heat treatment induced HO-1 expression and decreased copy number of HPV16 in cervical cancer cells and tissues from cervical cancer and precursor lesions. Knockdown of HO-1 stimulated autophagy accompanied by downregulation of X-linked inhibitor of apoptosis protein. Furthermore, silencing of HO-1 led to cell intolerance to hyperthermia, as manifested by inhibition of cell viability and induction of autophagic apoptosis. Moreover, HO-1 modulated hyperthermia-induced, autophagy-dependent antiviral effect. Thus, the findings indicate that blockade of HO-1 enhances hyperthermia-induced autophagy, an event resulting in apoptosis of cervical cancer cells through an antiviral mechanism. These observations imply the potential clinical utility of hyperthermia in combination with HO-1 inhibition in the treatment of cervical cancer.
热疗已被临床用作宫颈癌治疗的辅助疗法。然而，血红素加氧酶-1（HO-1）诱导的热耐受力限制了热疗的疗效，其确切机制尚不清楚。本研究发现，热处理诱导宫颈癌和癌前病变组织中宫颈癌细胞 HO-1 的表达和 HPV16 拷贝数降低。HO-1 的敲低刺激自噬，同时下调凋亡抑制蛋白 X 连锁。此外，沉默 HO-1 导致细胞对热不耐受，表现为细胞活力抑制和自噬凋亡诱导。此外，HO-1 调节热诱导的、自噬依赖性的抗病毒作用。因此，这些发现表明阻断 HO-1 增强了热诱导的自噬，通过抗病毒机制导致宫颈癌细胞凋亡。这些观察结果表明，热疗联合 HO-1 抑制在宫颈癌治疗中的潜在临床应用。
