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2019 ; 7
(13
): e14157
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TRPM7 is involved in acid-induced necrotic cell death in a manner sensitive to
progesterone in human cervical cancer cells
#MMPMID31293101
Numata T
; Sato-Numata K
; Okada Y
Physiol Rep
2019[Jul]; 7
(13
): e14157
PMID31293101
show ga
Because intravaginal pH is strongly acidic, it is important to investigate the
effects of acidosis on cervical cancer cells. Recently, in response to strong
acidosis, human cervical cancer HeLa cells were shown to exhibit necrosis after
showing persistent cell swelling induced by Cl(-) influx. Since cation influx
should be accompanied with Cl(-) influx to drive water inflow causing cell
swelling, we here studied on the nature of acidotoxic cation conductance. The
mRNA/protein expression was assessed by RT-PCR and Western blotting. Ionic
currents were measured by patch-clamping techniques. Cell counting/viability and
colorimetric assays were applied to assess proliferation rate and caspase 3/7
activity, respectively. Cell volume and size were measured by electronic sizing
and video-microscopic measurements, respectively. Acid exposure enhanced TRPM7
activity endogenously expressed in HeLa cells and exogenously overexpressed in
HEK293T cells. Gene silencing of TRPM7 abolished acid-induced cell swelling and
necrosis but rather induced activation of apoptotic caspase 3/7 in HeLa cells.
Overexpression with the pore charge-neutralizing D1054A mutant suppressed
acid-enhanced cation currents, acid-induced cell swelling, and acidotoxic
necrosis in HEK293T cells. Progesterone treatment was surprisingly found to
suppress molecular and functional expression of TRPM7 and cell proliferation in
HeLa cells. Furthermore, in the progesterone-treated cells, acid exposure did not
induce persistent cell swelling followed by necrosis but induced persistent cell
shrinkage and apoptotic cell death. These results indicate that in the human
cervical cancer cells, TRPM7 is essentially involved in acidotoxic necrotic cell
death, and progesterone inhibits TRPM7 expression thereby inhibiting acidotoxic
necrosis by switching to apoptosis.