mTORC1/2 inhibitor and curcumin induce apoptosis through lysosomal membrane permeabilization-mediated autophagy

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Mammalian target of rapamycin (mTOR) signaling is crucial for cell growth and dysregulated in cancer.
• mTOR forms complexes mTORC1 and mTORC2, both implicated in cancer progression.
• Targeting mTOR signaling is a key anti-cancer strategy, but single-agent efficacy varies.

Purpose of the Study:

• To investigate the efficacy of combining PP242, an mTOR inhibitor, with curcumin in treating human renal carcinoma.
• To elucidate the molecular mechanisms underlying PP242 and curcumin-induced cell death.
• To evaluate the therapeutic potential of this combination in preclinical cancer models.

Main Methods:

• Human renal carcinoma cells were treated with PP242 alone or in combination with curcumin.
• Cell viability, apoptosis markers (Bax, Mcl-1, Bcl-2), protein levels (Rictor, Akt), cytosolic Ca2+ release, lysosomal integrity, and autophagy were assessed.
• Overexpression of Rictor or Akt was used to confirm their roles.
• Tumor growth was evaluated in xenograft models.

Main Results:

• PP242 alone did not affect cell viability, but the combination with curcumin induced significant cell death.
• Combined treatment activated Bax, decreased Mcl-1 and Bcl-2 expression, and downregulated Rictor and Akt.
• Rictor downregulation led to increased cytosolic Ca2+ release, lysosomal damage, and subsequent autophagy.
• Overexpressing Rictor or Akt attenuated PP242 plus curcumin-induced cell death.
• Autophagy inhibition markedly reduced cell death.
• Combination treatment reduced tumor growth in xenograft models.

Conclusions:

• Combined PP242 and curcumin treatment effectively induces autophagy-mediated cell death in renal carcinoma.
• The mechanism involves downregulation of Rictor and Akt, leading to lysosomal damage and autophagy.
• This combination therapy shows promise for renal carcinoma treatment by targeting key survival pathways and inducing cell death via autophagy.