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Published on: October 28, 2019
Blocking tumor growth by targeting autophagy and SQSTM1 in vivo
1a Ohio State University Comprehensive Cancer Center ; Columbus , OH , USA.
Abstract:
Autophagy is a highly conserved cellular process for degradation of bulk cytoplasmic materials in response to starvation and maintenance of cellular homeostasis. Dysfunction of autophagy is implicated in a variety of diseases including cancer. In a recent study, we devised a system for inducible deletion of an essential autophagy gene Rb1cc1/Fip200 in established tumor cells in vivo and showed that Rb1cc1 is required for maintaining tumor growth. We further investigated the role of the accumulated SQSTM1 in Rb1cc1-null autophagy-deficient tumor cells. To our surprise, the increased SQSTM1 was not responsible for the inhibition of tumor growth, but rather supported the residual growth of tumors (i.e., partially compensated for the defective growth caused by Rb1cc1 deletion). Further analysis indicated that SQSTM1 promoted tumor growth in autophagy-deficient cells at least partially through its activation of the NFKB signaling pathway. A working model is proposed to account for our findings, which suggest that targeting both autophagy and the consequently increased SQSTM1 may be exploited for developing more effective cancer therapies.
Insights
Autophagy is crucial for cell health, and its dysfunction is linked to cancer. This study found that blocking autophagy gene Rb1cc1 in tumors unexpectedly increased SQSTM1, which supported tumor growth via NF-κB signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Autophagy is a fundamental cellular process essential for maintaining homeostasis.
- Autophagy dysfunction is implicated in various diseases, notably cancer.
- Rb1cc1 (Fip200) is an essential gene for autophagy, and its deletion impacts tumor growth.
Purpose of the Study:
- To investigate the role of Rb1cc1 deletion in established tumor cells.
- To determine the function of accumulated SQSTM1 in autophagy-deficient tumor cells.
- To explore novel therapeutic strategies targeting autophagy and SQSTM1 in cancer.
Main Methods:
- Developed an inducible system for Rb1cc1 deletion in vivo.
- Analyzed the impact of Rb1cc1 deletion on tumor growth and SQSTM1 accumulation.
- Investigated the signaling pathways affected by SQSTM1 in autophagy-deficient cells, including NF-κB.
Main Results:
- Rb1cc1 deletion inhibited tumor growth, as expected.
- Unexpectedly, accumulated SQSTM1 supported residual tumor growth in Rb1cc1-null cells.
- SQSTM1 promoted tumor growth, at least partially, by activating the NF-κB signaling pathway.
Conclusions:
- Rb1cc1 is essential for tumor growth, and its loss leads to autophagy deficiency.
- Accumulated SQSTM1 in autophagy-deficient cells has a pro-tumorigenic role.
- Targeting both autophagy and SQSTM1 may offer a promising therapeutic approach for cancer treatment.
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