Jinglu Wang1, Cassandra Garbutt2, Hangzhan Ma3, Peng Gao3, Francis J Hornicek3, Quancheng Kan4, Huirong Shi5, Zhenfeng Duan6. 1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. 2. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. 3. Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. 4. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. 5. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: hrshi2011@163.com. 6. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: zduan@mednet.ucla.edu.
Abstract
OBJECTIVE: Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. However, the role of p62 in drug resistance remains controversial. METHODS: In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues. The expression levels of p62 and autophagy related proteins were evaluated in two panels of human cancer cell lines by western blot. Cell viabilities were determined by MTT assay after exposure ovarian cancer cells to different concentrations of paclitaxel alone or in combination with autophagy inhibitors. RESULTS: Both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease-free survival and overall survival. Additionally, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, inhibition of autophagy enhanced paclitaxel sensitivity in drug resistant ovarian cancer cells. Furthermore, the wound healing assay exhibited that the inhibition of autophagy significantly decreased resistant ovarian cancer cell migration in vitro. CONCLUSION: Our findings highlight the potential of p62 as a new prognostic marker for ovarian cancer patients and p62's associated autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer.
OBJECTIVE: Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. However, the role of p62 in drug resistance remains controversial. METHODS: In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues. The expression levels of p62 and autophagy related proteins were evaluated in two panels of humancancer cell lines by western blot. Cell viabilities were determined by MTT assay after exposure ovarian cancer cells to different concentrations of paclitaxel alone or in combination with autophagy inhibitors. RESULTS: Both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease-free survival and overall survival. Additionally, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, inhibition of autophagy enhanced paclitaxel sensitivity in drug resistant ovarian cancer cells. Furthermore, the wound healing assay exhibited that the inhibition of autophagy significantly decreased resistant ovarian cancer cell migration in vitro. CONCLUSION: Our findings highlight the potential of p62 as a new prognostic marker for ovarian cancerpatients and p62's associated autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer.