CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling

Abstract

CIB1 is a 22-kDa regulatory protein previously implicated in cell survival and proliferation. However, the mechanism by which CIB1 regulates these processes is poorly defined. Here we report that CIB1 depletion in SK-N-SH neuroblastoma and MDA-MB-468 breast cancer cells promotes non-apoptotic, caspase-independent cell death that is not initiated by increased outer mitochondrial membrane permeability or translocation of apoptosis-inducing factor to the nucleus. Instead, cell death requires nuclear GAPDH accumulation. Furthermore, CIB1 depletion disrupts two commonly dysregulated, oncogenic pathways– PI3K/AKT and Ras/MEK/ERK, resulting in a synergistic mechanism of cell death, which was mimicked by simultaneous pharmacological inhibition of both pathways, but not either pathway alone. In defining each pathway’s contributions, we found that AKT inhibition alone maximally induced GAPDH nuclear accumulation, whereas MEK/ERK inhibition alone had no effect on GAPDH localization. Concurrent GAPDH nuclear accumulation and ERK inhibition were required however, to induce a significant DNA damage response, which was critical to subsequent cell death. Collectively, our results indicate that CIB1 is uniquely positioned to regulate PI3K/AKT and MEK/ERK signaling and that simultaneous disruption of these pathways synergistically induces a nuclear GAPDH-dependent cell death. The mechanistic insights into cell death induced by CIB1 interference suggest novel molecular targets for cancer therapy.

CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer

“…CIB1 is a small intracellular protein that regulates kinase activity and integrin biology [10–16], and has an emerging role in cancer cell survival and proliferation via regulation of oncogenic signaling pathways [10, 12, 14, 17, 18]. For example, CIB1 promotes AKT and ERK activation [10, 19], and may regulate these pathways via interaction with the serine/threonine kinase PAK1 [11, 20].…”

“…For example, CIB1 promotes AKT and ERK activation [10, 19], and may regulate these pathways via interaction with the serine/threonine kinase PAK1 [11, 20]. We recently showed that CIB1 depletion in two cancer cell lines (SK-N-SH neuroblastoma and MDA-MB-468 TNBC) disrupted both AKT and ERK signaling, resulting in the induction of a DNA damage response and a unique mechanism of non-apoptotic cell death [10]. …”

Calcium- and integrin-binding protein-1 is down-regulated in the sperm of patients with oligoasthenozoospermia

“…CIB1 binds to a number of potential effectors, such as PKD2 [18], AKT, ERK [19], PAK1 [20], PLK3 [21,22], and the functions of some of these proteins have been shown to be influenced by CIB1. These studies suggest that CIB1 regulates tumor growth, cell migration, endomitosis, and cell cycle progression.…”

The Emerging Roles of CIB1 in Cancer

“…Increasing evidence has suggested that CIB1 perform important roles in cell survival, cell proliferation, cell apoptosis and cell migration, thereby mediating tumor growth and angiogenesis [17, 20, 39-43]. CIB1 may serve an important role in tumorigenesis by regulating several kinase partners or oncogenic signaling (Table 1, 2 and Fig.…”

“…CIB1 is also implicated in cell survival and proliferation by modulating PI3K/AKT and MEK/ERK oncogenic signaling [41, 42]. Leisner et al have been identified that CIB1 depletion increased nuclear distribution of GAPDH by interrupting AKT and ERK signaling leading to caspase-independent cell death and proliferation inhibition [43]. Besides, CIB1 can associate with the catalytic subunit of human telomerase reverse transcriptase (hTERT), stimulating telomerase activity and telomere lengthening [53, 54].…”