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Published on: June 20, 2015
Relevance of mortalin to cancer cell stemness and cancer therapy
Chae-Ok Yun1, Priyanshu Bhargava2,3, Youjin Na1
1Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
Abstract:
Mortalin/mtHsp70 is a member of Hsp70 family of proteins. Enriched in a large variety of cancers, it has been shown to contribute to the process of carcinogenesis by multiple ways including inactivation of tumor suppressor p53 protein, deregulation of apoptosis and activation of EMT signaling. In this study, we report that upregulation of mortalin contributes to cancer cell stemness. Several cancer cell stemness markers, such as ABCG2, OCT-4, CD133, ALDH1, CD9, MRP1 and connexin were upregulated in mortalin-overexpressing cells that showed higher ability to form spheroids. These cells also showed higher migration, and were less responsive to a variety of cancer chemotherapeutic drugs. Of note, knockdown of mortalin by specific shRNA sensitized these cells to all the drugs used in this study. We report that low doses of anti-mortalin molecules, MKT-077 and CAPE, also caused similar sensitization of cancer cells to chemotherapeutic drugs and hence are potential candidates for effective cancer chemotherapy.
Insights
Mortalin protein promotes cancer stemness and resistance to chemotherapy. Reducing mortalin levels or using specific molecules sensitizes cancer cells to drugs, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Mortalin (mtHsp70) is implicated in carcinogenesis, affecting tumor suppressor p53, apoptosis, and EMT signaling.
- Its role in cancer cell stemness and chemoresistance is not fully understood.
Purpose of the Study:
- To investigate the role of mortalin upregulation in cancer cell stemness.
- To evaluate the impact of mortalin on cancer cell chemoresistance.
- To explore potential therapeutic strategies targeting mortalin.
Main Methods:
- Overexpression of mortalin in cancer cells.
- Knockdown of mortalin using shRNA.
- Assessment of cancer stemness markers (ABCG2, OCT-4, CD133, ALDH1, CD9, MRP1, connexin).
- Spheroid formation, migration assays, and drug sensitivity testing.
- Treatment with anti-mortalin molecules (MKT-077, CAPE).
Main Results:
- Mortalin overexpression led to increased cancer stemness markers and spheroid formation.
- Mortalin-overexpressing cells exhibited enhanced migration and reduced sensitivity to chemotherapeutic drugs.
- Knockdown of mortalin sensitized cancer cells to various drugs.
- Anti-mortalin agents MKT-077 and CAPE sensitized cancer cells to chemotherapy.
Conclusions:
- Mortalin upregulation contributes to cancer cell stemness and chemoresistance.
- Targeting mortalin with specific molecules or shRNA can re-sensitize cancer cells to chemotherapy.
- Anti-mortalin agents show potential as adjuncts in cancer chemotherapy.
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