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Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response ([UPR.sup.mt]), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous [UPR.sup.mt] to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the [UPR.sup.mt], heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATPproducing functions of mitochondria, which activated the [beta]-catenin pathway and led to the upregulation of c-Myc. We identified a [UPR.sup.mt] inhibitor that blocked HSP60's interaction with ClpP and abrogated survival signaling without altering HSP60's chaperonin function. Disruption of HSP60-ClpP interaction with the [UPR.sup.mt] inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the [UPR.sup.mt] inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP-mediated [UPR.sup.mt] is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa., Introduction Maintaining protein homeostasis (proteostasis) is essential for normal cellular functions and dysregulated proteostasis has been implicated in many types of cancer (1-3). Proteostasis is regulated by the unfolded protein [...]

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPRmt). The UPRmt system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPRmt is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPRmt. [ABSTRACT FROM AUTHOR]

An attempt is made to show that intracellular nucleotides as well as many nucleotide derivatives apply a strong inhibitory effect on the cytochrome c (CC)-initiated apoptosome formation by directly binding to CC and inhibiting the interaction of CC with Apaf-1. The results have indicated that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome the nucleotide barrier to undergo apoptosis cell death.