Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission

Abstract

Mitochondrial metabolism and dynamics (fission and fusion) critically regulate cell survival and proliferation, and abnormalities in these pathways are implicated in both neurodegenerative disorders and cancer. Mitochondrial fission is necessary for the growth of mutant Ras-dependent tumors. Here, we investigated whether loss of PTEN-induced kinase 1 (PINK1) - a mitochondrial kinase linked to recessive familial Parkinsonism - affects the growth of oncogenic Ras-induced tumor growth in vitro and in vivo. We show that RasG12D-transformed embryonic fibroblasts (MEFs) from PINK1-deficient mice display reduced growth in soft agar and in nude mice, as well as increased necrosis and decreased cell cycle progression, compared to RasG12D-transformed MEFs derived from wildtype mice. PINK1 re-expression (overexpression) at least partially rescues these phenotypes. Neither PINK1 deletion nor PINK1 overexpression altered Ras expression levels. Intriguingly, PINK1-deficient Ras-transformed MEFs exhibited elongated mitochondria and altered DRP1 phosphorylation, a key event in regulating mitochondrial fission. Inhibition of DRP1 diminished PINK1-regulated mitochondria morphological changes and tumor growth suggesting that PINK1 deficiency primarily inhibits Ras-driven tumor growth through disturbances in mitochondrial fission and associated cell necrosis and cell cycle defects. Moreover, we substantiate the requirement of PINK1 for optimal growth of Ras-transformed cells by showing that human HCT116 colon carcinoma cells (carrying an endogenous RasG13D mutation) with CRISPR/Cas9-introduced PINK1 gene deletions also show reduced mitochondrial fission and decreased growth. Our results support the importance of mitochondrial function and dynamics in regulating the growth of Ras-dependent tumor cells and provide insight into possible mechanisms underlying the lower incidence of cancers in Parkinson’s disease and other neurodegenerative disorders.

DDTC Suppresses Ovarian Cancer Development via the PI3K/AKT/mTOR Signaling Pathway

“…PTEN can modify other proteins and lipids through dephosphorylation. PTEN sends signals to cells to stop division and proceed to apoptosis, thus reducing tumor growth [ 13 , 14 ]. CCND1 has been recognized as a oncogene, and overexpression of CCND1 can lead to uncontrolled cell proliferation.…”

ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells

“…Herein, ARK5-WT cells demonstrated mitochondrial fission and higher phosphorylation of DRP1 [ 37 , 38 ] at serine 616 (DRP1 S616 ), and lower expression levels of MFN1, MFN2, and OPA1 (Fig. 5B ), similar to oncogenic RAS mutant–mediated phosphorylation of DRP1 S616 and mitochondrial fission in several human cancers, such as melanoma, and breast cancers [ 39 – 41 ]. Hence, DRP1 S616 phosphorylation can be a target for MM expressing ARK5.…”

Kinase signalling adaptation supports dysfunctional mitochondria in disease

“…Frontiers in Molecular Biosciences frontiersin.org 2015; Xie et al, 2015;Kitamura et al, 2017;Nagdas et al, 2019;Sessions et al, 2022;Zhu et al, 2022). Interestingly, the development of lung adenocarcinoma seems independent of DRP1 but is instead dependent upon the expression of OPA1 (Sessions et al, 2022).…”