S6K1 controls autophagosome maturation in autophagy induced by sulforaphane or serum deprivation

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Mammalian target of rapamycin complex 1 (mTORC1) signaling inhibits autophagy.
• The role of its downstream substrate, p70S6 kinase1 (S6K1), in autophagy regulation is controversial, with conflicting reports on its suppressive or promoting effects.

Purpose of the Study:

• To investigate the role of S6K1 in autophagy regulation in prostate cancer cells (PC-3) and mouse embryonic fibroblasts (MEF).
• To determine S6K1's function under autophagy-inducing conditions, such as sulforaphane treatment or serum deprivation.

Main Methods:

• Utilized prostate cancer cell line (PC-3) and mouse embryonic fibroblasts (MEF).
• Induced autophagy using sulforaphane (a cruciferous plant-derived isothiocyanate) and serum deprivation.
• Assessed autophagy markers, including LC3 processing and autophagosome/autophagolysosome formation, in the presence or absence of S6K1 activity or expression.

Main Results:

• Constitutively active S6K1 reduced LC3 processing and autophagosome formation in sulforaphane-treated cells.
• S6K1 presence was crucial for autophagosome maturation during induced autophagy (sulforaphane or serum deprivation).
• Reduced S6K1 levels or kinase activity led to autophagosome accumulation, decreased autophagolysosome numbers, and impaired autophagy flux under stress.
• Lack of S6 kinases diminished cell survival under stress conditions.

Conclusions:

• S6K1 plays a critical, context-dependent role in autophagy regulation.
• S6K1 is necessary for efficient autophagosome maturation and autophagy flux, particularly under cellular stress.
• S6K1 is important for stress-induced cell survival, highlighting its complex role beyond simple autophagy suppression.