Page 13 - Read Online

Page 8 of 27 J Cancer Metastasis Treat 2019;5:5 I http://dx.doi.org/10.20517/2394-4722.2018.108

In many tumors the signal transducer and activator of transcription (STAT) 3 has been found to be
constitutively active exerting two different functions, both required for cell transformation: (1) activating
transcription of its canonical target genes; and (2) regulating energy metabolism and mitochondrial
functions. These different activities are mediated by distinct phosphorylation events. In particular,
phosphorylation on residue Y705 is responsible for the nuclear activities, while phosphorylated S727 is
involved in regulating OXPHOS activities via mithocondrial localization.

We recently reported the localization of STAT3, in both its serine- and tyrosine-phosphorylated forms, to
the endoplasmic reticulum (ER) in breast cancer cell lines displaying constitutive activation of this factor.
2+
In these cells, S727-phosphorylated STAT3 is able to reduce ER Ca storage and release, thus contributing
2+
2+
to resistance to Ca mediated apoptosis upon oxidative stress stimuli. Indeed, Ca release from the ER
represents a crucial event in the regulation of life/death decision of cells, and its regulation is mainly exerted
by inositol 1,4,5-trisphosphate receptors, and in particular by type 3 (IP3R3), a calcium channel that in
response to IP3 stimulation allows Ca transfer from the ER to the mitochondrial associated membranes.
2+
We observed that STAT3 can physically interact with IP3R3. Moreover, STAT3 silencing increases IP3R3
expression by decreasing IP3R3 proteasoma-mediated degradation, suggesting that constitutively active
STAT3 can inhibit apoptosis by regulating IP3R3 abundance and activity. Accordingly, we found an inverse
correlation between IP3R3 and STAT3 protein levels in basal-like breast cancers, a cancer subtype that often
shows constitutive STAT3 activation. All together, these data indicate that S727-phosphorylated STAT3
2+
can promote IP3R3 degradation via direct interaction, thus reducing Ca exit from the ER and conferring
resistance to apoptosis.

Thus, in addition to the previously characterized nuclear and mitochondrial functions, we described a
novel contribution of STAT3 constitutive activation in conferring aggressiveness to breast cancer cells, and
in particular to basal-like breast cancers. This is exerted via localization of STAT3 to the ER, interaction
with IP3R3 and regulation of its degradation, that leads to decreased calcium release and thus resistance to
apoptosis.

11. Targeting acidic, nutritional and oxidative stresses in cancer

2
1
Ibtissam Marchiq , Masa Zdralevic , Milica Vucetic , Scott K. Parks , Jacques Pouysségur 1,2
2
1
1 Institute for Research on Cancer and Aging, Nice (IRCAN) University of Nice, Centre A. Lacassagne, 33
avenue de Valombrose, Nice 06189, France.
2 Medical Biology Department, Centre Scientifique de Monaco (CSM), Monaco 98000, France.

In metazoans, sensing the availability of oxygen and key nutrients (glucose, amino acids, fatty acids)
is integrated with growth factor and hormone signaling. This multiple nutrient and energy checkpoint
converges on the activation of the master protein kinase TORC1, critical for engaging cells in the cell cycle
and promoting growth. Cells have evolved sophisticated regulatory systems to rapidly respond to several
lethal stressors including metabolic acidosis, nutritional depletion and reactive oxygen species. Cancer
cells respond in multiple ways to escape and thrive these microenvironment stresses thus offering several
strategies to combat cancer resilience before and after therapeutic treatment.

In this lecture we will discuss how we can exploit cancer vulnerabilities (metabolic tumor acidosis, amino
acid depletion and oxidative stress) to propose novel anticancer targets capable to either arrest tumor growth
or to kill cancer cells.